Tyrosine kinase inhibitors

ABSTRACT

The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a sulfonyl indole moiety. The present invention is also related to the pharmaceutically acceptable salts, hydrates and stereoisomers of these compounds.

BACKGROUND OF THE INVENTION

Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering; cell growth, differentiation and proliferation; i.e., virtually all aspects of cell life, in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non life-threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer). PKs can be broken into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs).

Certain growth factor receptors exhibiting PK activity are known as receptor tyrosine kinases (RTKs). They comprise a large family of transmembrane receptors with diverse biological activity. As present, at least nineteen (19) distinct subfamilies of RTKs have been identified. One RTK subfamily contains the insulin receptor (IR), insulin-like growth factor I receptor (IGF-IR) and insulin receptor related receptor (IRR). IR and IGF-1R interact with insulin to activate a hetero-tetramer composed of two entirely extracellular glycosylated α subunits and two β subunits which cross the cell membrane and which contain the tyrosine kinase domain. The Insulin-like Growth Factor-1 Receptor (IGF-1R), and its ligands, IGF-1 and IGF-2, are abnormally expressed in numerous tumors, including, but not limited to, breast, prostate, thyroid, lung, hepatoma, colon, brain, neuroendocrine, and others.

A more complete listing of the known RTK subfamilies is described in Plowman et al., KN&P, 1994, 7(6):334-339 which is incorporated by reference, including any drawings, as if fully set forth herein.

In addition to the RTks, there also exists a family of entirely intracellular PTKs called “non-receptor tyrosine kinases” or “cellular tyrosine kinases.” This latter designation, abbreviated “CTK”, will be used herein. CTKs do not contain extracellular and transmembrane domains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Src subfamily appears so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detailed discussion of CTKs, see Bolen, Oncogene, 1993, 8:2025-2031, which is incorporated by reference, including any drawings, as if fully set forth herein.

represents an optional double bond;

X is C, N, S(O)_(m) or O; G is H₂ or O;

R^(a) is independently selected from:

1) H,

2) C₁-C₆ alkyl,

3) Halogen,

4) Aryl,

5) Heterocycle,

6) C₃-C₁₀ cycloalkyl, or

7) OR⁴;

said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent selected from R⁷; R¹ is independently selected from:

1) H,

RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including significantly, cancer. Other pathogenic conditions, which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, autoimmune diseases and a variety of renal disorders.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. The compounds of the instant invention possess a core structure that comprises a sulfonyl-indole moiety. The present invention is also related to the pharmaceutically acceptable salts and stereoisomers of these compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are useful in the inhibition of kinases and are illustrated by a compound of Formula I:

wherein Y is selected from:

2) (CR^(a) ₂)_(n)R⁶,

3) (CR^(a) ₂)_(n)C(O)R⁴,

4) C(O)N(R⁴)₂,

5) (CR^(a) ₂)_(n)OR⁴,

6) (CR^(a) ₂)_(n)N(R⁴)₂,

7) S(O)_(m)R⁶,

8) S(O)_(m)R⁶OR⁴,

9) C(O)N(R⁴)(CR^(a) ₂)_(n)R⁶,

10) C(O)N(R⁴)(CR^(a) ₂)_(n)OR⁴,

11) C(O)R⁶(CR^(a) ₂)_(n)R⁶,

12) C(O)N(R⁴)(CR^(a) ₂)_(n)S(O)_(m)(CR^(a) ₂)_(n)R⁶,

13) C(O)N(R⁴)(CR^(a) ₂)_(n)C(O)R⁶,

14) C(O)N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂,

15) Halogen,

16) N(R⁴)S(O)_(m)R⁶,

17) (CR^(a) ₂)_(n)C(O)OR⁴, and

18) R⁶C(O)OR;

R² is:

1) H,

2) unsubstituted or substituted C₁-C₁₀ alkyl,

3) N(R⁴)₂,

4) OR⁴,

5) unsubstituted or substituted aryl, and

6) unsubstituted or substituted C₃-C₁₀ cycloalkyl;

R⁴ is independently selected from:

1) H,

2) C₁-C₆ alkyl,

3) C₃-C₁₀ cycloalkyl,

4) Aryl,

5) Heterocycle,

6) CF₃,

7) C₂-C₆ alkenyl, and

8) C₂-C₆ alkynyl;

said alkyl, cycloalkyl, aryl, heterocycle, alkenyl and alkynyl is optionally substituted with at least one substituent selected from R⁷; R⁵ is independently selected from:

1) H,

2) Halogen,

3) NO₂,

4) CN,

5) CR⁴═C(R⁴)₂,

6) C≡CR⁴

7) (CR^(a) ₂)_(n)OR⁴

8) (CR^(a) ₂)_(n)N(R⁴)₂,

9) C(O)R⁴,

10) C(O)OR⁴,

11) (CR^(a) ₂)_(n)R⁴,

12) S(O)_(m)R⁶,

13) S(O)_(m)N(R⁴)₂,

14) OS(O)_(m)R⁶,

15) N(R⁴)C(O)R⁴,

16) N(R⁴)S(O)_(m)R⁶,

17) (CR^(a) ₂)_(n)N(R⁴)R⁶,

18) (CR^(a) ₂)_(n)N(R⁴)R⁶OR⁴,

19) (CR^(a) ₂)_(n)N(R⁴)(CR^(a) ₂)_(n)C(O)N(R⁴)₂,

20) N(R⁴)(CR^(a) ₂)_(n)R⁶,

21) N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂,

22) (CR^(a) ₂)_(n)C(O)N(R⁴)₂,

23) O(CR^(a) ₂)_(n)C(O)OR⁴, and

24) O(CR^(a) ₂)_(n)C(O)N(R⁴)₂;

R⁶ is independently selected from:

1) C₁-C₆ alkyl,

2) Aryl,

3) Heterocycle, and

4) C₃-C₁₀ cycloalkyl;

said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent of R⁷; R⁷ is independently selected from:

1) Unsubstituted or substituted C₁-C₆ alkyl,

2) Halogen,

3) OR⁴,

4) CF₃,

5) Unsubstituted or substituted aryl,

6) Unsubstituted or substituted C₃-C₁₀ cycloalkyl,

7) Unsubstituted or substituted heterocycle,

8) S(O)_(m)N(R⁴)₂,

9) C(O)OR⁴,

10) C(O)R⁴,

11) CN,

12) C(O)N(R⁴)₂,

13) N(R⁴)C(O)R⁴,

14) NO₂; and

15) S(O)_(m)R⁶;

m is independently 0, 1 or 2; n is independently 0, 1, 2, 3, 4, 5 or 6; s is 0 to 6; t is 0, 1, or 2; v is 0, 1 or 2; w is 0, 1, 2, 3 or 4; z is 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof.

A second embodiment of the instant invention is a compound of Formula II:

wherein:

represents an optional double bond;

X is C, N, S(O)_(m) or O; G is H₂ or O;

R^(a) is independently selected from:

1) H,

2) C₁-C₆ alkyl,

3) Halogen,

4) Aryl,

5) Heterocycle,

6) C₃-C₁₀ cycloalkyl, and

7) OR⁴;

said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent selected from R⁷; R¹ is independently selected from:

1) H,

2) (CR^(a) ₂)_(n)R⁶,

3) (CR^(a) ₂)_(n)C(O)R⁴,

4) C(O)N(R⁴)₂,

5) (CR^(a) ₂)_(n)OR⁴,

6) (CR^(a) ₂)_(n)N(R⁴)₂,

7) S(O)_(m)R⁶,

8) S(O)_(m)R⁶OR⁴,

9) C(O)N(R⁴)(CR^(a) ₂)_(n)R⁶,

10) C(O)N(R⁴)(CR^(a) ₂)_(n)OR⁴,

11) C(O)R⁶(CR^(a) ₂)_(n)R⁶,

12) C(O)N(R⁴)(CR^(a) ₂)_(n)S(O)_(m)(CR^(a) ₂)_(n)R⁶,

13) C(O)N(R⁴)(CR^(a) ₂)_(n)C(O)R⁶,

14) C(O)N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂,

15) Halogen,

16) N(R⁴)S(O)_(m)R⁶,

17) (CR^(a) ₂)_(n)C(O)OR⁴, and

18) R⁶C(O)OR;

R² is:

1) H,

2) Unsubstituted or substituted C₁-C₁₀ alkyl,

3) N(R⁴)₂, or

4) OR⁴;

R⁴ is independently selected from:

1) H,

2) C₁-C₆ alkyl,

3) C₃-C₁₀ cycloalkyl,

4) Aryl,

5) Heterocycle,

6) CF₃,

7) C₂-C₆ alkenyl, and

8) C₂-C₆ alkynyl;

said alkyl, cycloalkyl, aryl, heterocycle, alkenyl and alkynyl is optionally substituted with at least one substituent selected from R⁷; R⁵ is independently selected from:

1) H,

2) Halogen,

3) NO₂,

4) CN,

5) CR⁴═C(R⁴)₂,

6) C≡CR⁴

7) (CR^(a) ₂)_(n)OR⁴

8) (CR^(a) ₂)_(n)N(R⁴)₂,

9) C(O)R⁴,

10) C(O)OR⁴,

11) (CR^(a) ₂)_(n)R⁴,

12) S(O)_(m)R⁶,

13) S(O)_(m)N(R⁴)₂,

14) OS(O)_(m)R⁶,

15) N(R⁴)C(O)R⁴,

16) N(R⁴)S(O)_(m)R⁶,

17) (CR^(a) ₂)_(n)N(R⁴)R⁶,

18) (CR^(a) ₂)_(n)N(R⁴)R⁶OR⁴,

19) (CR^(a) ₂)_(n)N(R⁴)(CR^(a) ₂)_(n)C(O)N(R⁴)₂,

20) N(R⁴)(CR^(a) ₂)_(n)R⁶,

21) N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂, and

22) (CR^(a) ₂)_(n)C(O)N(R⁴)₂;

R⁶ is independently selected from:

1) C₁-C₆ alkyl,

2) Aryl,

3) Heterocycle, and

4) C₃-C₁₀ cycloalkyl;

said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent of R⁷; R⁷ is independently selected from:

1) Unsubstituted or substituted C₁-C₆ alkyl,

2) Halogen,

3) OR⁴,

4) CF₃,

5) Unsubstituted or substituted aryl,

6) Unsubstituted or substituted C₃-C₁₀ cycloalkyl,

7) Unsubstituted or substituted heterocycle,

8) S(O)_(m)N(R⁴)₂,

9) C(O)OR⁴,

10) C(O)R⁴,

11) CN,

12) C(O)N(R⁴)₂,

13) N(R⁴)C(O)R⁴,

14) S(O)_(m)R⁶, and

15) NO₂;

m is independently 0, 1 or 2; n is independently 0, 1, 2, 3, 4, 5 or 6; s is 0 to 6; t is 0, 1, or 2; v is 0, 1 or 2; w is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt or stereoisomer thereof.

A third embodiment of the instant invention is a compound of Formula II, as described above, wherein:

R^(a) is independently selected from:

1) H,

2) C₁-C₆ alkyl,

3) Aryl, and

4) C₃-C₁₀ cycloalkyl;

said alkyl, aryl, and cycloalkyl is optionally substituted with at least one substituent selected from R⁷; R¹ is independently selected from:

1) H,

2) (CR^(a) ₂)_(n)R⁶,

3) (CR^(a) ₂)_(n)C(O)R⁴,

4) C(O)N(R⁴)₂,

5) (CR^(a) ₂)_(n)OR⁴,

6) (CR^(a) ₂)_(n)N(R⁴)₂,

7) S(O)_(m)R⁶,

8) S(O)_(m)R⁶OR⁴,

9) C(O)N(R⁴)(CR^(a) ₂)_(n)R⁶,

10) C(O)N(R⁴)(CR^(a) ₂)_(n)OR⁴,

11) N(R⁴)S(O)_(m)R⁶,

12) (CR^(a) ₂)_(n)C(O)OR⁴, and

13) R⁶C(O)OR;

R² is:

1) N(R⁴)₂, or

2) OR⁴;

s is 0 to 3; and all other substituents and variables are as defined in the second embodiment; or a pharmaceutically acceptable salt or stereoisomer thereof.

A further embodiment of the third embodiment is a compound of Formula II, as described above, wherein:

R¹ is independently selected from:

1) H,

2) (CR^(a) ₂)_(n)R⁶,

3) (CR^(a) ₂)_(n)C(O)R⁴,

4) C(O)N(R⁴)₂,

5) (CR^(a) ₂)_(n)OR⁴,

6) (CR^(a) ₂)_(n)N(R⁴)₂,

7) S(O)_(m)R⁶, and

8) S(O)_(m)R⁶OR⁴;

and all other substituents and variables are as defined in the third embodiment; or a pharmaceutically acceptable salt or stereoisomer thereof.

Examples of compounds of the instant invention include

-   5-Chloro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   6-Methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-(Methylsulfonyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-nitro-1H-indole-2-carboxamide; -   5-Chloro-3-(piperazin-1-ylsulfonyl)-1H-indole-2-carboxamide; -   3-[(4-Benzylpiperazin-1-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide; -   3-[(4-Acetylpiperazin-1-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide; -   5-Chloro-3-(piperidin-1-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Chloro-3-(pyrrolidin-1-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Chloro-3-(thiomorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Azetidin-1-ylsulfonyl)-5-chloro-1H-indole-2-carboxamide; -   5-Chloro-3-[(oxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Chloro-3-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   cis-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   trans-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Chloro-3-[(3-hydroxyazetidin-1-yl)sulfonyl]-1H-indole-2-carboxamide; -   (±)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (S)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (R)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-({4-[2-(dimethylamino)ethyl]-5-oxo-1,4-diazepan-1-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-({5-oxo-1,4-diazepan-1-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-[(3-oxopiperazin-1-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(3-hydroxyazetidin-1-yl)sulfonyl]-1H-indole-2-carboxamide; -   (±)-5-Bromo-3-{[2-(aminocarbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   3-(Azetidin-1-ylsulfonyl)-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-({4-[(4-bromophenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-{[4-(3-morpholin-4-ylpropyl)-3-oxopiperazin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-({4-[3-(dimethylamino)propyl]-3-oxopiperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-(2,5-dihydroxy-1H-pyrrol-1-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-(6-oxa-3-azabicyclo[3.1.0]hex-3-ylsulfonyl)-1H-indole-2-carboxamide; -   (±)-5-Bromo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (S)-5-Bromo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (R)-5-Bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   6-Hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-(2-Furyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-(2-phenylethyl)-1H-indole-2-carboxamide; -   5-Hex-1-ynyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Hexyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   Methyl     2-(aminocarbonyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-5-carboxylate; -   3-(Morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide; -   5-Hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Ethoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-propoxy-1H-indole-2-carboxamide; -   5-Isopropoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Ethyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   2-(Aminocarbonyl)-3-(morpholin-4-ylsulfonyl)-1H-indol-5-yl     methanesulfonate; -   3-(Morpholin-4-ylsulfonyl)-5-prop-1-ynyl-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-thien-2-yl-1H-indole-2-carboxamide; -   3-(Azetidin-1-ylsulfonyl)-5-methoxy-1H-indole-2-carboxamide; -   5-Formyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Methyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-(Acetylamino)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-[(Methylsulfonyl)amino]-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-{[(4-Methoxyphenyl)amino]methyl}-3-morpholino-4-ylsulfonyl)     1H-indole-2-carboxamide; -   5-{[(2-Acetamide)amino]methyl}-3-morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholino-4-ylsulfonyl)-5-phenyl-1H-indole-2-carboxamide; -   3-(Morpholino-4-ylsulfonyl)-5-pyrazin-2-yl-1H-indole-2-carboxamide; -   3-(Morpholino-4-ylsulfonyl)-5-pyridin-2-yl-1H-indole-2-carboxamide; -   3-(Morpholino-4-ylsulfonyl)-5-pyridin-4-yl-1H-indole-2-carboxamide; -   5-(1-Benzofuran-2-yl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-(5-Methyl-2-furyl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-(3,5-Dimethylisoxazole-4-yl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-(1H-pyrrol-2-yl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-pyridin-3-yl-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-(1,3-thiazol-2-yl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-thien-3-yl-1H-indole-2-carboxamide; -   5-(1-Benzothien-3-yl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Azetidin-1-yl}sulfonyl)-5-iodo-1H-indole-2-carboxamide; -   3-[(3-Hydroxyazetidin-1-yl)sulfonyl]-5-iodo-1H-indole-2-carboxamide; -   (±)-5-Iodo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (S)-5-Iodo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (R)-5-Iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   7-Amino-6-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-Amino-4,6-dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   6-Bromo-7-(dimethylamino)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-7-[(pyridin-4-ylmethyl)amino]-1H-indole-2-carboxamide; -   7-{[(2-Chloropyridin-4-yl)methyl]amino}-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-Nitro-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   7-Amino-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   3-{[(2S)-2-(Phenoxymethyl)morpholin-4-yl]sulfonyl}-7-[(pyridin-4-ylmethyl)amino]-1H-indole-2-carboxamide; -   7-(Benzylamino)-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   7-Chloro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   6-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-Cyano-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   (±)-7-(Methylsulfinyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   7-Aminomethyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   (S)-5-Fluoro-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   (R)-5-Fluoro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Acetylamino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-[(Methylsulfonyl)amino]-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   3-(Morpholin-4-ylsulfonyl)-5-[(trifluoroacetyl)amino]-1H-indole-2-carboxamide; -   5-[(2-Aminoethyl)amino]-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-(Dimethylamino)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   4,5-Dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5,6-Dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-6-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-6-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-4-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide; -   (S)-3-{[2-(Phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(cyclohexylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(2,3-dihydro-1H-inden-1-ylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-phenylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(3-phenylpropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(3,3-diphenylpropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-phenoxyethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   3-({2-[(3-Benzylpyrrolidin-1-yl)carbonyl]morpholin-4-yl}sulfonyl)-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(1,2,3,4-tetrahydronaphthalen-2-ylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   3-({2-[(Benzylamino)carbonyl]morpholin-4-yl}sulfonyl)-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({[3-(trifluoromethyl)benzyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2,2-diphenylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(2,3-dihydro-1H-inden-2-ylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   7-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}-2-benzyl-7-aza-2-azoniaspiro[4.4]nonane; -   5-Bromo-3-{[2-({[(5-methylpyrazin-2-yl)methyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   3-({[(4-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}morpholin-2-yl)carbonyl]amino}methyl)pyridine; -   5-Bromo-3-[(2-{[(1-phenylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   1-(3-{[(4-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}morpholin-2-yl)carbonyl]amino}propyl)-1H-imidazole; -   5-Bromo-3-{[2-({[(IR)-1-phenylethyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-phenylpropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   3-[(2-{[Benzyl(methyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-5-bromo-1H-indole-2-carboxamide; -   1-[(4-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}morpholin-2-yl)carbonyl]-4-benzylpiperazine; -   2-({[(4-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}morpholin-2-yl)carbonyl]amino}methyl)pyridine; -   5-Bromo-3-{[2-({[2-(tert-butylthio)ethyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   3-({2-[(Benzhydrylamino)carbonyl]morpholin-4-yl}sulfonyl)-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({[(2S)-2-phenylcyclopropyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(3-phenylpyrrolidin-1-yl)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(4,4-diphenylpiperidin-1-yl)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2,3-dihydro-1H-inden-2-ylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(2,3-dihydro-1H-inden-1-ylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(2,3-dihydro-1H-inden-1-ylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(3-pyridin-4-ylpyrrolidin-1-yl)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   3-{[2-(Anilinocarbonyl)morpholin-4-yl]sulfonyl}-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-oxo-2-phenylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[(neopentylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(1,2-diphenylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(4-chlorophenyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(4-phenoxyphenyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(4-tert-butylphenyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(3-isopropoxypropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(3-ethoxypropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-cyclohex-1-en-1-ylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2,2,3,3,4,4,4-heptafluorobutyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(3-isobutoxypropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(3-butoxypropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-thien-2-ylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   2-({[(4-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}morpholin-2-yl)carbonyl]amino}methyl)-1H-benzimidazole; -   3-{[2-(Azepan-1-ylcarbonyl)morpholin-4-yl]sulfonyl}-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-({2-[({2-[(2,6-dichlorobenzyl)thio]ethyl}amino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   3-{[2-({[4-(Aminosulfonyl)benzyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-5-bromo-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-(thiomorpholin-4-ylcarbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-methoxyethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-methoxy-1-methylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(1-ethylpropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({[6-(dimethylamino)hexyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(tetrahydrofuran-2-ylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(1-phenylcyclopropyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({[phenyl(pyridin-4-yl)methyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(dicyclopropylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(1,4-dioxan-2-ylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({methyl[2-(4-methylphenoxy)ethyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-{[2-({[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[2-(2-phenylethyl)pyrrolidin-1-yl]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(2-cyclohexylethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   4-({[(4-{[2-(Aminocarbonyl)-5-bromo-1H-indol-3-yl]sulfonyl}morpholin-2-yl)carbonyl]amino}methyl)-1-methyl-1H-imidazole; -   5-Bromo-3-[(2-{[(1,1-dioxidotetrahydrothien-3-yl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(1-naphthylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   5-Bromo-3-[(2-{[(imidazo[2,1-b][1,3]thiazol-6-ylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide; -   3-[(2-{[2-(1,3-Benzothiazol-2-yl)pyrrolidin-1-yl]carbonyl}morpholin-4-yl)sulfonyl]-5-bromo-1H-indole-2-carboxamide; -   5-Chloro-3-({2-[(2-ethoxyphenoxy)methyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   5-Chloro-3-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylsulfonyl]-1H-indole-2-carboxamide; -   7-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}-3-benzyl-9-thia-7-aza-3-azoniabicyclo[3.3.1]nonane; -   5-Chloro-3-{[2-(1H-indol-4-yl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Chloro-3-(2,3-dihydro-1,4-benzoxazepin-4(5H)-ylsulfonyl)-1H-indole-2-carboxamide; -   3-[(Benzofuran-yl-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide; -   5-Chloro-3-{[4-fluoro-4-(3-phenylpropyl)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   3-[(3-Benzyl-1-oxa-8-azaspiro[4.5]dec-8-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide; -   3-({4-[(Benzyloxy)methyl]-4-phenylpiperidin-1-yl}sulfonyl)-5-chloro-1H-indole-2-carboxamide; -   5-Chloro-3-{[4-hydroxy-4-(3-phenylpropyl)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   7-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}-2-(4-chlorophenyl)-7-aza-2-azoniaspiro[4.4]nonane; -   3-(1-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}piperidin-3-yl)-4-methyl-4H-1,2,4-triazole; -   5-Chloro-3-{[3-(2-phenylethyl)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Chloro-3-{[3-(2-phenylethyl)pyrrolidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Chloro-3-{[4-(cyclopropyl     {[3-(trifluoromethyl)phenyl]sulfonyl}amino)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Chloro-3-({2-[(4-chlorophenoxy)methyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide; -   Tert-butyl     (1-{[2-(aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}piperidin-3-yl)acetate; -   3-[(3-Benzylpiperidin-1-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide; -   5-Chloro-3-{[3-(2-methylphenyl)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   2-(1-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}piperidin-4-yl)-N,N-dimethylethanamine; -   1-(1-{[2-(Aminocarbonyl)-5-chloro-1H-indol-3-yl]sulfonyl}piperidin-4-yl)-3-(ethoxycarbonyl)piperidine; -   5-Bromo-3-{[3-(4-tert-butoxybenzyl)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-3-{[4-(3-phenylpropyl)piperidin-1-yl]sulfonyl}-1H-indole-2-carboxamide; -   5-Bromo-N-methoxy-N-methyl-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide;     or the pharmaceutically acceptable salts or stereoisomers thereof.

Specific examples of compounds of the instant invention include

3-(Morpholin-4-ylsulfonyl)-5-(1,3-thiazol-2-yl)-1H-indole-2-carboxamide

(S)-5-Iodo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

5-Bromo-6-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

5-bromo-3-({2-[(2,3-dihydro-1H-inden-2-ylamino)carbonyl]morpholin-4-yl}sulfonyl)-1H-indole-2-carboxamide

5-bromo-3-{[2-({[2-(tert-butylthio)ethyl]amino}carbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

5-bromo-3-[(2-{[(1-naphthylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide

or a pharmaceutically acceptable salt or stereoisomer thereof.

The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted or named.

When any variable (e.g. aryl, heterocycle, R¹, R^(a) etc.) occurs more than one time in any substituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds.

Lines drawn into the ring systems from substituents (such as from R¹, R⁵, etc.) indicate that the indicated bond may be attached to any of the substitutable ring carbon atoms or heteroatoms, including the carbon atom or heteroatom that is the point of attachment. If the ring system is polycyclic, such as

it is intended that the bond may be attached to any of the suitable carbon atoms or heteroatoms of any ring. It is also intended that a moiety such as

could also be represented as:

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.

As used herein, “alkyl” is intended to include both branched and straight-chain aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀ alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀ alkyl” specifically includes methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.

“Cycloalkyl” as used herein is intended to include non-aromatic cyclic hydrocarbon groups, having the specified number of carbon atoms, which may or may not be bridged or structurally constrained. Examples of such cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl, tetrahydro-naphthalene, methylenecylohexyl, and the like. As used herein, examples of “C₃-C₁₀ cycloalkyl” may include, but are not limited to:

As used herein, the term “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

If no number of carbon atoms is specified, the term “alkenyl” refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, “C₂-C₆ alkenyl” means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.

The term “alkynyl” refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to 3 carbon-carbon triple bonds may be present. Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.

As used herein, “aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, indanyl, indanonyl, indenyl, biphenyl, tetralinyl, tetralonyl, fluorenonyl, phenanthryl, anthryl, acenaphthyl, tetrahydronaphthyl, and the like.

As appreciated by those of skill in the art, “halo” or “halogen” as used herein is intended to include chloro, fluoro, bromo and iodo.

The term heteroaryl, as used herein, represents a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzimidazolyl, benzodioxolyl, benzotriazolyl, benzothiofuranyl, benzothiazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, benzoquinolinol, imidazolyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrahydronaphthyl, tetrahydroquinoline, and the like.

The term heterocycle or heterocyclic or heterocyclyl, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. “Heterocycle” or “heterocyclyl” therefore includes the above mentioned heteroaryls, as well as dihydro and tetrahydro analogs thereof. Further examples of “heterocyclyl” include, but are not limited to the following: azepanyl, azetidinyl, benzimidazolyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzopyranyl, benzopyrazolyl, benzotriazolyl, benzothiazolyl, benzothienyl, benzothiofuranyl, benzothiophenyl, benzothiopyranyl, benzoxazepinyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl, diazepanyl, diazapinonyl, dihydrobenzofuranyl, dihydrobenzofuryl, dihydrobenzoimidazolyl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrocyclopentapyridinyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisoquinolinyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dioxanyl, dioxidotetrahydrothienyl, dioxidothiomorpholinyl, furyl, furanyl, imidazolyl, imidazolinyl, imidazolidinyl, imidazothiazolyl, imidazopyridinyl, indazolyl, indolazinyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolinyl, isoquinolinone, isoquinolyl, isothiazolyl, isothiazolidinyl, isoxazolinyl, isoxazolyl, methylenedioxybenzoyl, morpholinyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, oxetanyl, oxoazepinyl, oxadiazolyl, oxidothiomorpholinyl, oxodihydrophthalazinyl, oxodihydroindolyl, oxoimidazolidinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxopyrimidinyl, oxopyrrolyl, oxatriazolyl, piperidyl, piperidinyl, piperazinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinoyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, quinazolinyl, quinolinyl, quinolyl, quinolinonyl, quinoxalinyl, tetrahydrocycloheptapyridinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiazolinyl, thienofuryl, thienyl, thiomorpholinyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, and the like. Preferably, heterocycle is selected from oxoazepinyl, benzimidazolyl, diazepanyl, diazapinonyl, imidazolyl, oxoimidazolidinyl, indolyl, isoquinolinyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidinyl, oxopiperidinyl, oxopyrimidinyl, oxopyrrolidinyl, quinolinyl, tetrahydrofuryl, tetrahydrofuranyl, tetrahydroisoquinolinyl, thienyl, furyl, furanyl, pyrazinyl, benzofuranyl, isoxazolyl, pyrrolyl, thiazolyl, benzothienyl, dihydroisoquinolinyl, azepanyl, thiomorpholinyl, dioxanyl, dioxidotetrahydrothienyl, imidazothiazolyl, benzothiazolyl, and triazolyl.

As used herein, “aralkyl” is intended to mean an aryl moiety, as defined above, attached through a C₁-C₁₀ alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphthylmethyl and phenylpropyl.

As used herein, “heterocyclylalkyl” is intended to mean a heterocyclic moiety, as defined below, attached through a C₁-C₁₀ alkyl linker, where alkyl is defined above. Examples of heterocyclylalkyls include, but are not limited to, pyridylmethyl, imidazolylethyl, pyrrolidinylmethyl, morpholinylethyl, quinolinylmethyl, imidazolylpropyl and the like.

As used herein, the terms “substituted C₁-C₁₀ alkyl” and “substituted C₁-C₆ alkoxy” are intended to include the branch or straight-chain alkyl group of the specified number of carbon atoms, wherein the carbon atoms may be substituted with 1 to 3 substituents selected from the group which includes, but is not limited to, halo, C₁-C₂₀ alkyl, CF₃, NH₂, N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N₃, —OH, —O(C₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆ alkyl) S(O)₀₋₂—, (C₀-C₆ alkyl)S(O)₀₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)C(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₀-C₆ alkyl)C(O)—, (C₀-C₆ alkyl)OC(O)—, (C₀-C₆ alkyl)O(C₁-C₆ alkyl)-, (C₀-C₆ alkyl)C(O) 1-2(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)OC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl.

As used herein, the terms “substituted C₃-C₁₀ cycloalkyl”, “substituted aryl”, “substituted heterocycle”, “substituted aralkyl” and “substituted heterocyclylalkyl” are intended to include the cyclic group containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound. Preferably, the substituents are selected from the group which includes, but is not limited to, halo, C₁-C₂₀ alkyl, CF₃, NH₂, N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N₃, —OH, —O(C₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, (C₀-C₆ alkyl)S(O)₀₋₂—, (C₀-C₆ alkyl)S(O)₀₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)C(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₀-C₆ alkyl)C(O)—, (C₀-C₆ alkyl)OC(O)—, (C₀-C₆alkyl)O(C₁-C₆ alkyl)-, (C₀-C₆ alkyl)C(O)₁₋₂(C₀-C₆ alkyl)-, (C₀-C₆ alkyl)OC(O)NH—, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl.

As used herein, the phrase “substituted with at least one substituent” is intended to mean that the substituted group being referenced has from 1 to 6 substituents. Preferably, the substituted group being referenced contains from 1 to 3 substituents, in addition to the point of attachment to the rest of the compound.

Preferably, R² is OR⁴ or NR⁴ ₂. Most preferably, R² is N(R⁴)₂.

Preferably, G is H₂.

Preferably, X is O, N or C. More preferably, X is O or N. Most preferably, X is O.

Preferably, n is independently 0, 1, 2, 3 or 4. More preferably, n is independently 0, 1 or 2.

Preferably, s and w are independently 0, 1, 2, 3 or 4. More preferably, s is 0, 1 or 2. More preferably, w is 0, 1, 2 or 3.

Preferably, t and v are independently 0 or 1.

It is intended that the definition of any substituent or variable (e.g., R¹, R^(a), n, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, —N(R⁴)₂ represents —NHH, —NHCH₃, —NHC₂H₅, etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials.

For use in medicine, the salts of the compounds of Formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. When the compound of the present invention is acidic, suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N,N¹-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19.

It will also be noted that the compounds of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.

Abbreviations, which may be used in the description of the chemistry and in the Examples that follow, include:

Ac₂O Acetic anhydride; AcOH Acetic acid;

AIBN 2,2′-Azobisisobutyronitrile; Ar Aryl;

BINAP 2,2′-Bis(diphenylphosphino)-1,1′ binaphthyl;

Bn Benzyl;

BOC/Boc tert-Butoxycarbonyl;

BSA Bovine Serum Albumin; CAN Ceric Ammonia Nitrate; CBz Carbobenzyloxy; CI Chemical Ionization;

DBAD Di-tert-butyl azodicarboxylate; DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene;

DCC 1,3-Dichlorohexylcarbodiimide; DCE 1,2-Dichloroethane; DCM Dichloromethane; DIEA N,N-Diisopropylethylamine; DMAP 4-Dimethylaminopyridine; DME 1,2-Dimethoxyethane; DMF N,N-Dimethylformamide;

DMSO Methyl sulfoxide; DPPA Diphenylphosphoryl azide;

DTT Dithiothreitol;

EDC 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide-hydrochloride; EDTA Ethylenediaminetetraacetic acid;

ELSD Evaporative Light Scattering Detector; ES Electrospray;

ESI Electrospray ionization; Et₂O Diethyl ether;

Et₃N Triethylamine;

EtOAc Ethyl acetate;

EtOH Ethanol; FAB Fast Atom Bombardment;

HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid;

HMPA Hexamethylphosphoramide;

HOAc Acetic acid; HOBt 1-Hydroxybenzotriazole hydrate; HOOBt 3-Hydroxy-1,2,2-benzotriazin-4(3H)-one; HPLC High-performance liquid chromatography;

HRMS High Resolution Mass Spectroscopy;

KOtBu Potassium tert-butoxide; LAH Lithium aluminum hydride;

LCMS Liquid Chromatography Mass Spectroscopy;

MCPBA m-Chloroperoxybenzoic acid;

Me Methyl; MeOH Methanol;

MP-Carbonate Macroporous polystyrene carbonate;

Ms Methanesulfonyl; MS Mass Spectroscopy;

MsCl Methanesulfonyl chloride; n-Bu n-butyl; n-Bu₃P Tri-n-butylphosphine; NaHMDS Sodium bis(trimethylsilyl)amide;

NBS N-Bromosuccinimide; NMM N-methylmorpholine; NMR Nuclear Magnetic Resonance;

Pd(PPh₃)₄ Palladium tetrakis(triphenylphosphine); Pd2(dba)₃ Tris(dibenzylideneacetone)dipalladium (0); Ph phenyl; PMSF α-Toluenesulfonyl fluoride; PS-DCC Polystyrene dicyclohexylcarbodiimide; PS-DMAP Polystyrene dimethylaminopyridine;

PS-NMM Polystyrene N-methylmorpholine; Py or pyr Pyridine;

PYBOP Benzotriazol-1-yloxytripyrrolidinophosphonium (or PyBOP) hexafluorophosphate;

RPLC Reverse Phase Liquid Chromatography; RT Room Temperature; SCX SPE Strong Cation Exchange Solid Phase Extraction;

t-Bu tert-Butyl; TBAF Tetrabutylammonium fluoride; TBSCl tert-Butyldimethylsilyl chloride; TFA Trifluoroacetic acid;

THF Tetrahydrofuran; TIPS Triisopropylsilyl; TMS Tetramethylsilane; and Tr Trityl. Utility

In another aspect, this present invention relates to a method of modulating the catalytic activity of PKs (protein kinases) in a mammal in need thereof comprising contacting the PK with a compound of Formula I.

As used herein, the term “modulation” or “modulating” refers to the alteration of the catalytic activity of receptor tyrosine kinases (RTKs), cellular tyrosine kinases (CTKs) and serine-threonine kinases (STKs). In particular, modulating refers to the activation of the catalytic activity of RTKs, CTKs and STKs, preferably the activation or inhibition of the catalytic activity of RTKs, CTKs and STKs, depending on the concentration of the compound or salt to which the RTKs, CTKs or STKs is exposed or, more preferably, the inhibition of the catalytic activity of RTKs, CTKs and STKs.

The term “catalytic activity” as used herein refers to the rate of phosphorylation of tyrosine under the influence, direct or indirect, of RTKs and/or CTKs or the phosphorylation of serine and threonine under the influence, direct or indirect, of STKs.

The term “contacting” as used herein refers to bringing a compound of this invention and a target PK together in such a manner that the compound can affect the catalytic activity of the PK, either directly; i.e., by interacting with the kinase itself, or indirectly; i.e., by interacting with another molecule on which the catalytic activity of the kinase is dependent. Such “contacting” can be accomplished “in vitro,” i.e., in a test tube, a petri dish or the like. In a test tube, contacting may involve only a compound and a PK of interest or it may involve whole cells. Cells may also be maintained or grown in cell culture dishes and contacted with a compound in that environment. In this context, the ability of a particular compound to affect a PK related disorder; i.e., the IC₅₀ of the compound, defined below, can be determined before use of the compounds in vivo with more complex living organisms is attempted. For cells outside the organism, multiple methods exist, and are well known to those skilled in the art, to get the PKs in contact with the compounds including, but not limited to, direct cell microinjection and numerous transmembrane carrier techniques.

The above-referenced PK is selected from the group comprising an RTK, a CTK or an STK in another aspect of this invention. Preferably, the PK is an RTK.

Furthermore, it is an aspect of this invention that the receptor tyrosine kinase (RTK) whose catalytic activity is modulated by a compound of this invention is selected from the group comprising EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-1R, FGFR-3R and FGFR-4R. Preferably, the RTK is preferably, the receptor protein kinase is selected from IR, IGF-1R, or IRR.

In addition, it is an aspect of this invention that the cellular tyrosine kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk.

Another aspect of this invention is that the serine-threonine protein kinase whose catalytic activity is modulated by a compound of this invention is selected from the group consisting of CDK2 and Raf.

In another aspect, this invention relates to a method for treating or preventing a PK-related disorder in a mammal in need of such treatment comprising administering to the mammal a therapeutically effective amount of one or more of the compounds described above.

As used herein, “PK-related disorder,” “PK driven disorder,” and “abnormal PK activity” all refer to a condition characterized by inappropriate (i.e., diminished or, more commonly, excessive) PK catalytic activity, where the particular PK can be an RTK, a CTK or an STK. Inappropriate catalytic activity can arise as the result of either: (1) PK expression in cells which normally do not express PKs; (2) increased PK expression leading to unwanted cell proliferation, differentiation and/or growth; or, (3) decreased PK expression leading to unwanted reductions in cell proliferation, differentiation and/or growth. Excessive-activity of a PK refers to either amplification of the gene encoding a particular PK or its ligand, or production of a level of PK activity which can correlate with a cell proliferation, differentiation and/or growth disorder (that is, as the level of the PK increases, the severity of one or more symptoms of a cellular disorder increase as the level of the PK activity decreases).

“Treat,” “treating” or “treatment” with regard to a PK-related disorder refers to alleviating or abrogating the cause and/or the effects of a PK-related disorder.

As used herein, the terms “prevent”, “preventing” and “prevention” refer to a method for barring a mammal from acquiring a PK-related disorder in the first place.

The term “administration” and variants thereof (e.g., “administering” a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), “administration” and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.

The term “therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

The term “treating cancer” or “treatment of cancer” refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.

The protein kinase-related disorder may be selected from the group comprising an RTK, a CTK or an STK-related disorder in a further aspect of this invention. Preferably, the protein kinase-related disorder is an RTK-related disorder.

In yet another aspect of this invention, the above referenced PK-related disorder may be selected from the group consisting of an EGFR-related disorder, a PDGFR-related disorder, an IGFR-related disorder and a flk-related disorder.

The above referenced PK-related disorder may be a cancer selected from, but not limited to, astrocytoma, basal or squamous cell carcinoma, brain cancer, glioblastoma, bladder cancer, breast cancer, colorectal cancer, chondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thyoma, thyroid cancer, testicular cancer and osteosarcoma in a further aspect of this invention. More preferably, the PK-related disorder is a cancer selected from brain cancer, breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma or endometrial carcinoma.

Included within the scope of the present invention is a pharmaceutical composition, which is comprised of a compound of Formula I as described above and a pharmaceutically acceptable carrier. The present invention also encompasses a method of treating or preventing cancer in a mammal in need of such treatment which is comprised of administering to said mammal a therapeutically effective amount of a compound of Formula I. Types of cancers which may be treated using compounds of Formula I include, but are not limited to, astrocytoma, basal or squamous cell carcinoma, brain cancer, glioblastoma, bladder cancer, breast cancer, colorectal cancer, chondrosarcoma, cervical cancer, adrenal cancer, choriocarcinoma, esophageal cancer, endometrial carcinoma, erythroleukemia, Ewing's sarcoma, gastrointestinal cancer, head and neck cancer, hepatoma, glioma, hepatocellular carcinoma, leukemia, leiomyoma, melanoma, non-small cell lung cancer, neural cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, rhabdomyosarcoma, small cell lung cancer, thymona, thyroid cancer, testicular cancer and osteosarcoma in a further aspect of this invention. More preferably, the cancer being treated is selected from breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma, or endometrial carcinoma.

The above-referenced PK-related disorder may be an IGFR-related disorder selected from diabetes, an autoimmune disorder, Alzheimer's and other cognitive disorders, a hyperproliferation disorder, aging, cancer, acromegaly, Crohn's disease, endometriosis, diabetic retinopathy, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis in yet another aspect of this invention.

A method of treating or preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of Formula I is also encompassed by the present invention. Methods of treating or preventing ocular diseases, such as diabetic retinopathy and age-related macular degeneration, are also part of the invention.

Also included within the scope of the present invention is a method of treating or preventing inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions, as well as treatment or prevention of bone associated pathologies selected from osteosarcoma, osteoarthritis, and rickets.

Other disorders which might be treated with compounds of this invention include, without limitation, immunological and cardiovascular disorders such as atherosclerosis.

The invention also contemplates the use of the instantly claimed compounds in combination with a second compound selected from the group consisting of:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) angiogenesis inhibitor.

A preferred angiogenesis inhibitor is selected from the group consisting of a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MMP inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, and an antibody to VEGF. Preferred estrogen receptor modulators are tamoxifen and raloxifene.

Also included in the scope of the claims is a method of treating cancer, which comprises administering a therapeutically effective amount of a compound of Formula I in combination with a compound selected from the group consisting of:

1) an estrogen receptor modulator,

2) an androgen receptor modulator,

3) retinoid receptor modulator,

4) a cytotoxic agent,

5) an antiproliferative agent,

6) a prenyl-protein transferase inhibitor,

7) an HMG-CoA reductase inhibitor,

8) an HIV protease inhibitor,

9) a reverse transcriptase inhibitor, and

10) angiogenesis inhibitor.

And yet another embodiment is the method of treating cancer using the combination discussed above, in combination with radiation therapy.

And yet another embodiment of the invention is a method of treating cancer which comprises administering a therapeutically effective amount of a compound of Formula I in combination with paclitaxel or trastuzumab. The PKs whose catalytic activity is modulated by the compounds of this invention include protein tyrosine kinases of which there are two types, receptor tyrosine kinases (RTKs) and cellular tyrosine kinases (CTKs), and serine-threonine kinases (STKs). RTK-mediated signal transduction, is initiated by extracellular interaction with a specific growth factor (ligand), followed by receptor dimerization (or conformational changes in the case of IR, IGF-1R or IRR), transient stimulation of the intrinsic protein tyrosine kinase activity, autophosphorylation and subsequent phosphorylation of other substrate proteins. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, metabolic effects on the extracellular microenvironment, etc.). See Schlessinger and Ullrich, 1992, Neuron 9:303-391.

It has been shown that tyrosine phosphorylation sites, on growth factor receptors, function as high-affinity binding sites for SH2 (src homology) domains of signaling molecules. Fantl et al., 1992, Cell 69:413-423; Songyang et al., 1994, Mol., Cell. Biol. 14:2777-2785); Songyang et al., 1993, Cell 72:767-778; and Koch et al., 1991, Science 252:668-678. Another signaling molecule domain, which interacts with phosphorylated tyrosines, is termed a PTB domain. Blaikie et al., 1994, J. Biol. Chem. 269:32031-32034; Gustafson et al., 1995, Mol. Cell. Biol., 15:2500-25008; Kavanaugh and Williams, 1994, Science 266:1862-1865. Several intracellular substrate proteins that associate with RTKs have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such domain, but which serve as adapters and associate with catalytically active molecules. Songyang et al., 1993, Cell 72:767-778. The specificity of the interactions between receptors and SH2 domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the binding affinities between SH2 or PTB domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors are consistent with the observed differences in their substrate phosphorylation profiles. Songyang et al., 1993, Cell 72:767-778. These observations suggest that the function of each RTK is determined not only by its pattern of expression and ligand availability, but also by the array of downstream signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory step, which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.

STKs, being primarily cytosolic, affect the internal biochemistry of the cell, often as a down-stream response to a PTK event. STKs have been implicated in the signaling process which initiates DNA synthesis and subsequent mitosis leading to cell proliferation.

Thus, PK signal transduction results in, among other responses, cell proliferation, differentiation, growth, metabolism, and cellular mobility. Abnormal cell proliferation may result in a wide array of disorders and diseases, including the development of neoplasia such as carcinoma, sarcoma, glioblastoma and hemangioma, disorders such as leukemia, psoriasis, arteriosclerosis, arthritis and diabetic retinopathy and other disorders related to uncontrolled angiogenesis and/or vasculogenesis.

A precise understanding of the mechanism by which the compounds of this invention inhibit PKs is not required in order to practice the present invention. However, while not hereby being bound to any particular mechanism or theory, it is believed that the compounds interact with the amino acids in the catalytic region of PKs. PKs typically possess a bi-lobate structure wherein ATP appears to bind in the cleft between the two lobes in a region where the amino acids are conserved among PKs. Inhibitors of PKs are believed to bind by non-covalent interactions such as hydrogen bonding, van der Waals forces and ionic interactions in the same general region where the aforesaid ATP binds to the PKs. The compounds disclosed herein may have utility as in vitro assays for such proteins as well as exhibiting in vivo therapeutic effects through interaction with such proteins.

In another aspect, the protein kinase (PK), the catalytic activity of which is modulated by contact with a compound of this invention, is a protein tyrosine kinase (PTK), more particularly, a receptor protein tyrosine kinase (RTK). Among the RTKs whose catalytic activity can be modulated with a compound of this invention, or salt thereof, are, without limitation, EGF, HER2, HER3, HER4, IR, IGF-1R, IRR, PDGFRα, PDGFRβ, TrkA, TrkB, TrkC, HGF, CSFIR, C-Kit, C-fms, Flk-1R, Flk4, KDR/Flk-1, Flt-1, FGFR-1R, FGFR-2R, FGFR-3R and FGFR-4R. Most preferably, the RTK is selected from IGF-1R.

The protein tyrosine kinase whose catalytic activity is modulated by contact with a compound of this invention, or a salt or a prodrug thereof, can also be a non-receptor or cellular protein tyrosine kinase (CTK). Thus, the catalytic activity of CTKs such as, without limitation, Src, Frk, Btk, Csk, Abl, ZAP70, Fes, Fps, Fak, Jak, Ack, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, may be modulated by contact with a compound or salt of this invention.

Still another group of PKs which may have their catalytic activity modulated by contact with a compound of this invention are the serine-threonine protein kinases such as, without limitation, CDK2 and Raf.

This invention is also directed to compounds that modulate PK signal transduction by affecting the enzymatic activity of RTKs, CTKs and/or STKs, thereby interfering with the signals transduced by such proteins. More particularly, the present invention is directed to compounds which modulate RTK, CTK and/or STK mediated signal transduction pathways as a therapeutic approach to cure many kinds of solid tumors, including, but not limited to, carcinomas, sarcomas including Kaposi's sarcoma, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Treatment or prevention of non-solid tumor cancers such as leukemia are also contemplated by this invention. Indications may include, but are not limited to brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreatic cancers, colon cancers, blood cancers, breast cancers, prostrate cancers, renal cell carcinomas, lung cancer and bone cancers.

Further examples, without limitation, of the types of disorders related to inappropriate PK activity that the compounds described herein may be useful in preventing, treating and studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders.

As previously mentioned, the Insulin-like Growth Factor-1 Receptor (IGF-1R) belongs to the family of transmembrane tyrosine kinase receptors such as platelet-derived growth factor receptor, the epidermal growth factor receptor, and the insulin receptor. There are two known ligands for the IGF-1R receptor. They are IGF-1 and IGF-2. As used herein, the term “IGF” refers to both IGF-1 and IGF-2. The insulin-like growth factor family of ligands, receptors and binding proteins is reviewed in Krywicki and Yee, Breast Cancer Research and Treatment, 22:7-19, 1992.

IGF/IGF-1R driven disorders are characterized by inappropriate or over-activity of IGF/IGF-1R. Inappropriate IGF activity refers to either: (1) IGF or IGF-IR expression in cells which normally do not express IGF or IGF-1R; (2) increased IGF or IGF-1R expression leading to unwanted cell proliferation such as cancer; (3) increased IGF or IGF-1R activity leading to unwanted cell proliferation, such as cancer; and/or over-activity of IGF or IGF-1R. Over-activity of IGF or IGF-IR refers to either an amplification of the gene encoding IGF-1, IGF-2, IGF-1R or the production of a level of IGF activity which can be correlated with a cell proliferative disorder (i.e., as the level of IGF increases the severity of one or more of the symptoms of the cell proliferative disorder increases) the bioavailability of IGF-1 and IGF-2 can also be affected by the presence or absence of a set of IGF binding presence or absence of a set of IGF binding proteins (IGF BPs) of which there are six know. Over activity of IGF/IGF-1R can also result from a down regulation of IGF-2 which contains an IGF-2 binding domain, but no intracellular kinase domain. Examples of IGF/IGF-1R driven disorders include the various IGF/IGF-1R related human malignancies reviewed in Cullen, et al., Cancer Investigation, 9(4):443-454, 1991, incorporated herein by reference in its entirety, including any drawings. IGF/IGF-1Rs clinical importance and role in regulating osteoblast function is reviewed in Schmid, Journal of Internal Medicine, 234:535-542, 1993.

Thus, IGF-1R activities include: (1) phosphorylation of IGF-1R protein; (2) phosphorylation of an IGF-1R protein substrate; (3) interaction with an IGF adapter protein; (4) IGF-IR protein surface expression. Additional IGF-1R protein activities can be identified using standard techniques. IGF-1R activity can be assayed by measuring one or more of the following activities: (1) phosphorylation of IGF-1R; (2) phosphorylation of an IGF-1R substrate; (3) activation of an IGF-1R adapter molecule; and (4) activation of downstream signaling molecules, and/or (5) increased cell division. These activities can be measured using techniques described below and known in the arts.

IGF-1R has been implicated as an absolute requirement for the establishment and maintenance of the transformed phenotype both in vitro and in vivo in several cell types (R. Baserga, Cancer Research 55:249-252, 1995). Herbimycin A has been said to inhibit the IGF-1R protein tyrosine kinase and cellular proliferation in human breast cancer cells (Sepp-Lorenzino, et al., 1994, J Cell Biochem. Suppl. 18b: 246). Experiments studying the role of IGF-1R in transformation have used antisense strategies, dominant negative mutants, and antibodies to the IGF-1R and have led to the suggestion that IGR-1R may be a preferred target for therapeutic interventions.

IGF-1R, in addition to being implicated in nutritional support and in type-II diabetes, has also been associated with several types of cancers. For example, IGF-I has been implicated as an autocrine growth stimulator for several tumor types, e.g. human breast cancer carcinoma cells (Arteago et al., J. Clin. Invest., 1989, 84:1418-1423) and small lung tumor cells (Macauley et al., Cancer Res., 1989, 50:2511-2517). In addition, IGF-1, while integrally involved in the normal growth and differentiation of the nervous system, also appears to be an autocrine stimulator of human gliomas. Sandberg-Nordqvist et al., Cancer Res., 1993, 53:2475-2478.

An example of IGF-2's potential involvement in colorectal cancer may be found in the up-regulation of IGF-2 mRNA in colon tumors relative to normal color tissue. (Zhang et al., Science (1997) 276:1268-1272.) IGF-2 may also play a role in hypoxia induced neovascularization of tumors. (Minet et al., Int. J. Mol. Med. (2000) 5:253-259.) IGF-2 may also play a role in tumorigenesis through activation of an insulin receptor isoform-A. IGF-2 activation of insulin receptor isoform-A activates cell survival signaling pathways in cells but its relative contribution to tumor cell growth and survival is unknown at this time. Insulin receptor isoform-A's kinase domain is identical to the standard insulin receptor's. Scalia et al., 2001, J. Cell Biochem. 82:610-618.

The importance of IGF-1R and its ligands in cell types in culture (fibroblasts, epithelial cells, smooth muscle cells, T-lymphocytes, myeloid cells, chondrocytes and osteoblasts (the stem cells of the bone marrow)) is illustrated by the ability of IGF-1 to stimulate cell growth and proliferation. Goldring and Goldring, Eukaryotic Gene Expression, 1991, 1:301-326. In a series of recent publications, Baserga and others suggests that IGF-1R plays a central role in the mechanism of transformation and, as such, could be a preferred target for therapeutic interventions for a broad spectrum of human malignancies. Baserga, Cancer Res., 1995, 55:249-252; Baserga, Cell, 1994, 79:927-930; Coppola et al., Mol. Cell. Biol., 1994, 14:4588-4595; Baserga, Trends in Biotechnology, 1996, 14:150-152; H. M. Khandwala et al., Endocrine Reviews, 21:215-244, 2000. The predominant cancers that may be treated using a compound of the instant invention include, but are not limited to breast cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma, or endometrial carcinoma.

IGF-1 has also been associated with retinal neovascularization. Proliferative diabetes retinopathy has been seen in some patients having high levels of IGF-1. (L. E. Smith et al., Nature Medicine, 1999, 5:1390-1395.)

Compounds of the instant invention may also be useful as anti-aging agents. It has been observed that there is a link between IGF signalling and aging. Experiments have shown that calorie-restricted mammals have low levels of insulin and IGF-1 and have a longer life span. Similar observations have been made for insects as well. (See C. Kenyon, Cell, 2001, 105:165-168; E. Strauss, Science, 2001, 292:41-43; K. D. Kimura et al., Science 1997, 277:942-946; M. Tatar et al., Science, 2001, 292:107-110).

STKs have been implicated in many types of cancer including, notably, breast cancer (Cance et al., Int. J. Cancer, 1993, 54:571-77).

The association between abnormal PK activity and disease is not restricted to cancer. For example, RTKs have been associated with diseases such as psoriasis, diabetes mellitus, endometriosis, angiogenesis, atheromatous plaque development, Alzheimer's disease, epidermal hyperproliferation, neurodegenerative diseases, age-related macular degeneration and hemangiomas. For example, EGFR has been indicated in corneal and dermal wound healing. Defects in Insulin-R and IGF-1R are indicated in type-II diabetes mellitus. A more complete correlation between specific RTKs and their therapeutic indications is set forth in Plowman et al., DN&P, 1994, 7:334-339.

As noted previously, not only RTKs but CTKs including, but not limited to, src, abl, fps, yes, fyn, lyn, lck, Zap70, blk, hck, fgr and yrk (reviewed by Bolen et al., FASEB J., 1993, 6:3403-3409) are involved in the proliferative and metabolic signal transduction pathway and thus could be expected, and have been shown, to be involved in may PTK-mediated disorders to which the present invention is directed. For example, mutated src (v-src) has been shown to be an oncoprotein (pp 60^(v-src)) in chicken. Moreover, its cellular homolog, the protooncogene pp 60^(c-src) transmits oncogenic signals of many receptors. Over-expression of EGFR or HER2/neu in tumors leads to the constitutive activation of pp 60^(c-src), which is characteristic of malignant cells, but absent in normal cells. On the other hand, mice deficient in the expression of c-src exhibit an osteopetrotic phenotype, indicating a key participation of c-src in osteoclast function and a possible involvement in related disorders.

Similarly, Zap70 has been implicated in T-cell signaling which may relate to autoimmune disorders.

STKs have been associated with inflammation, autoimmune disease, immunoresponses, and hyperproliferation disorders such as restenosis, fibrosis, psoriasis, osteoarthritis and rheumatoid arthritis.

PKs have also been implicated in embryo implantation. Thus, the compounds of this invention may provide an effective method of preventing such embryo implantation and thereby be useful as birth control agents.

Finally, both RTKs and CTKs are currently suspected as being involved in hyperimmune disorders.

These and other aspects of the invention will be apparent from the teachings contained herein.

A method for identifying a chemical compound that modulates the catalytic activity of one or more of the above discussed protein kinases is another aspect of this invention. The method involved contacting cells expressing the desired protein kinase with a compound of this invention (or its salt or prodrug) and monitoring the cells for any effect that the compound has on them. The effect may be any observable, either to the naked eye or through the use of instrumentation, change or absence of change in a cell phenotype. The change or absence of change in the cell phenotype monitored may be, for example, without limitation, a change or absence of change in the catalytic activity of the protein kinase in the cells or a change or absence of change in the interaction of the protein kinase with a natural binding partner.

Composition

Pharmaceutical compositions of the above compounds are a further aspect of this invention.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The present invention also encompasses a pharmaceutical composition useful in the treatment of cancer, comprising the administration of a therapeutically effective amount of the compounds of this invention, with or without pharmaceutically acceptable carriers or diluents. Suitable compositions of this invention include aqueous solutions comprising compounds of this invention and pharmacologically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may be introduced into a patient's bloodstream by local bolus injection.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.

The compounds of the instant invention may also be co-administered with other well-known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. For example, in the case of bone-related disorders, combinations that would be useful include those with antiresorptive bisphosphonates, such as alendronate and risedronate; integrin blockers (defined further below), such as α_(v)β₃ antagonists; conjugated estrogens used in hormone replacement therapy, such as PREMPRO®, PREMARIN® and ENDOMETRION®; selective estrogen receptor modulators (SERMs), such as raloxifene, droloxifene, CP-336,156 (Pfizer) and lasofoxifene; cathespin K inhibitors; and ATP proton pump inhibitors.

The instant compounds are also useful in combination with known anti-cancer agents. Such known anti-cancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angiogenesis inhibitors. The instant compounds are particularly useful when coadministered with radiation therapy. The synergistic effects of inhibiting VEGF in combination with radiation therapy have been described in the art. (see WO 00/61186.)

“Estrogen receptor modulators” refers to compounds, which interfere or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Androgen receptor modulators” refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds, which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, α-difluoromethylornithine, ILX23-7553, trans-N-(4′-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.

“Cytotoxic agents” refer to compounds which cause cell death primarily by interfering directly with the cell's functioning or inhibit or interfere with cell myosis, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.

Examples of cytotoxic agents include, but are not limited to, tirapazamine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, doxorubicin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, porfiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro) platinum (II)]tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3′-deamino-3′-morpholino-13-deoxo-10-hydroxycaminomycin, annamycin, galarubicin, elinafide, MEN10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesine sulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, and BMS188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3′,4′-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b, 7]indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2′-dimethylamino-2′-deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa, 9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]-phenanthradinium, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthene-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, and dimesna.

“Antiproliferative agents” includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2′-deoxy-2′-methylidenecytidine, 2′-fluoromethylene-2′-deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl cytosine, and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferative agents” also includes monoclonal antibodies to growth factors, other than those listed under “angiogenesis inhibitors”, such as trastuzumab, and tumor suppressor genes, such as p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example).

“HMG-CoA reductase inhibitors” refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which have inhibitory activity for HMG-CoA reductase can be readily identified by using assays well-known in the art. For example, see the assays described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131 at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor of HMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (MEVACOR®, see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039); simvastatin (ZOCOR®, see U.S. Pat. Nos. 4,444,784, 4,820,850 and 4,916,239); pravastatin (PRAVACHOL®, see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589); fluvastatin (LESCOL®, see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896); atorvastatin (LIPITOR®, see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952); and cerivastatin (also known as rivastatin and BAYCHOL®, see U.S. Pat. No. 5,177,080). The structural formulae of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention. An illustration of the lactone portion and its corresponding open-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term “HMG-CoA reductase inhibitor” as used herein. Preferably, the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin. Herein, the term “pharmaceutically acceptable salts” with respect to the HMG-CoA reductase inhibitor shall mean non-toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine, piperazine, and tris(hydroxymethyl)aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.

“Prenyl-protein transferase inhibitor” refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase). Examples of prenyl-protein transferase inhibiting compounds include (±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, (−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, 5(S)-n-butyl-1-(2,3-dimethylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, (S)-1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-5-[2-(ethanesulfonyl)methyl)-2-piperazinone, 5(S)-n-Butyl-1-(2-methylphenyl)-4-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-2-piperazinone, 1-(3-chlorophenyl)-4-[1-(4-cyanobenzyl)-2-methyl-5-imidazolylmethyl]-2-piperazinone, 1-(2,2-diphenylethyl)-3-[N-(1-(4-cyanobenzyl)-1H-imidazol-5-ylethyl)carbamoyl]piperidine, 4-{5-[4-hydroxymethyl-4-(4-chloropyridin-2-ylmethyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile, 4-{5-[4-hydroxymethyl-4-(3-chlorobenzyl)-piperidine-1-ylmethyl]-2-methylimidazol-1-ylmethyl}benzonitrile, 4-{3-[4-(2-oxo-2H-pyridin-1-yl)benzyl]-3H-imidazol-4-ylmethyl}benzonitrile, 4-{3-[4-(5-chloro-2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile, 4-{3-[4-(2-oxo-2H-[1,2′]bipyridin-5′-ylmethyl]-3H-imidazol-4-ylmethyl}benzonitrile, 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl}benzonitrile, 18,19-dihydro-19-oxo-5H,17H-6, 10:12,16-dimetheno-1H-imidazo[4,3-c][1,11,4]dioxaazacyclo-nonadecine-9-carbonitrile, (±)-19,20-dihydro-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecine-9-carbonitrile, 19,20-dihydro-19-oxo-5H,17H-18,21-ethano-6, 10:12,16-dimetheno-22H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile, and (±)-19,20-dihydro-3-methyl-19-oxo-5H-18,21-ethano-12,14-etheno-6,10-metheno-22H-benzo[d]imidazo[4,3-k][1,6,9,12]oxa-triazacyclooctadecine-9-carbonitrile.

Other examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No. 9, pp. 1394-1401 (1999).

Examples of HIV protease inhibitors include amprenavir, abacavir, CGP-73547, CGP-61755, DMP-450, indinavir, nelfinavir, tipranavir, ritonavir, saquinavir, ABT-378, AG 1776, and BMS-232,632. Examples of reverse transcriptase inhibitors include delaviridine, efavirenz, GS-840, HB Y097, lamivudine, nevirapine, AZT, 3TC, ddC, and ddI.

“Angiogenesis inhibitors” refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1) and Flk-1/KDR (VEGFR20), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-α, interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p. 573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol., Vol. 16, p. 107 (1996); Jpn. J. Pharmacol., Vol. 75, p. 105 (1997); Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF. (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

As described above, the combinations with NSAID's are directed to the use of NSAID's which are potent COX-2 inhibiting agents. For purposes of this specification an NSAID is potent if it possess an IC₅₀ for the inhibition of COX-2 of 1 μM or less as measured by the cell or microsomal assay disclosed herein.

The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC₅₀ for COX-2 over IC₅₀ for COX-1 evaluated by the cell or microsomal assay disclosed hereinunder. Such compounds include, but are not limited to those disclosed in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, U.S. Pat. No. 6,020,343, issued Feb. 1, 2000, U.S. Pat. No. 5,409,944, issued Apr. 25, 1995, U.S. Pat. No. 5,436,265, issued Jul. 25, 1995, U.S. Pat. No. 5,536,752, issued Jul. 16, 1996, U.S. Pat. No. 5,550,142, issued Aug. 27, 1996,

U.S. Pat. No. 5,604,260, issued Feb. 18, 1997, U.S. Pat. No. 5,698,584, issued Dec. 16, 1997, U.S. Pat. No. 5,710,140, issued Jan. 20, 1998, WO 94/15932, published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999, all of which are hereby incorporated by reference.

Inhibitors of COX-2 that are particularly useful in the instant method of treatment are:

3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and

5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine;

or a pharmaceutically acceptable salt thereof.

General and specific synthetic procedures for the preparation of the COX-2 inhibitor compounds described above are found in U.S. Pat. No. 5,474,995, issued Dec. 12, 1995, U.S. Pat. No. 5,861,419, issued Jan. 19, 1999, and U.S. Pat. No. 6,001,843, issued Dec. 14, 1999, all of which are herein incorporated by reference.

Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, the following:

or a pharmaceutically acceptable salt thereof.

Compounds, which are described as specific inhibitors of COX-2 and are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications, which are herein incorporated by reference: WO 94/15932, published Jul. 21, 1994, U.S. Pat. No. 5,344,991, issued Jun. 6, 1994, U.S. Pat. No. 5,134,142, issued Jul. 28, 1992, U.S. Pat. No. 5,380,738, issued Jan. 10, 1995, U.S. Pat. No. 5,393,790, issued Feb. 20, 1995, U.S. Pat. No. 5,466,823, issued Nov. 14, 1995, U.S. Pat. No. 5,633,272, issued May 27, 1997, and U.S. Pat. No. 5,932,598, issued Aug. 3, 1999.

Compounds which are specific inhibitors of COX-2 and are therefore useful in the present invention, and methods of synthesis thereof, can be found in the following patents, pending applications and publications, which are herein incorporated by reference: U.S. Pat. No. 5,474,995 issued Dec. 12, 1995, U.S. Pat. No. 5,861,419 issued Jan. 19, 1999, U.S. Pat. No. 6,001,843 issued Dec. 14, 1999, U.S. Pat. No. 6,020,343 issued Feb. 1, 2000, U.S. Pat. No. 5,409,944 issued Apr. 25, 1995, U.S. Pat. No. 5,436,265 issued Jul. 25, 1995, U.S. Pat. No. 5,536,752 issued Jul. 16, 1996, U.S. Pat. No. 5,550,142 issued Aug. 27, 1996, U.S. Pat. No. 5,604,260 issued Feb. 18, 1997, U.S. Pat. No. 5,698,584 issued Dec. 16, 1997, and U.S. Pat. No. 5,710,140 issued Jan. 20, 1998.

Other examples of angiogenesis inhibitors include, but are not limited to, endostation, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1H-1,2,3-triazole-4-carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonyl-imino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).

As used above, “integrin blockers” refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the α_(v)β₃ integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the α_(v)β3 integrin and the α_(v)β₅ integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the αvβ₆, αvβ₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The term also refers to antagonists of any combination of αvβ₃, αvβ₅, αvβ₆, αvβ₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins.

Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylindenyl)indolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1H-diindolo[1,2,3-fg: 3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one, SH268, genistein, STI571, CEP2563, 4-(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and EMD121974.

The instant compounds are also useful, alone or in combination with platelet fibrinogen receptor (GP IIb/IIIa) antagonists, such as tirofiban, to inhibit metastasis of cancerous cells. Tumor cells can activate platelets largely via thrombin generation. This activation is associated with the release of VEGF. The release of VEGF enhances metastasis by increasing extravasation at points of adhesion to vascular endothelium (Amirkhosravi, Platelets 10, 285-292, 1999). Therefore, the present compounds can serve to inhibit metastasis, alone or in combination with GP IIb/IIIa) antagonists. Examples of other fibrinogen receptor antagonists include abciximab, eptifibatide, sibrafiban, lamifiban, lotrafiban, cromofiban, and CT50352.

Formulations

The compounds of this invention may be administered to mammals, preferably humans, either alone or, preferably, in combination with pharmaceutically acceptable carriers, excipients or diluents, optionally with known adjuvants, such as alum, in a pharmaceutical composition, according to standard pharmaceutical practice. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and/or topical routes of administration.

If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds of the instant invention may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

For oral use of a compound according to this invention, particularly for chemotherapy, the selected compound may be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and cornstarch, and lubricating agents, such as magnesium stearate, are commonly added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled in order to render the preparation isotonic.

Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.

The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.

The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)

The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

When a compound according to this invention is administered into a human subject, the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms.

In one exemplary application, a suitable amount of compound is administered to a mammal undergoing treatment for cancer. Administration occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.

The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. These schemes, therefore, are not limited by the compounds listed nor by any particular substituents employed for illustrative purposes. Substituent numbering, as shown in the schemes, does not necessarily correlate to that used in the claims.

As shown in the schemes below, the term “phosphine” includes, but is not limited to, tri-substituted phosphines. Examples of tri-substituted phosphines include, but are not limited to, dppf, dppe, dppp, trialkyl phosphines (such as triphenyl phosphine, tributyl phosphine, triorthortoluoyl phosphine, etc.) and the like.

EXAMPLES

Examples provided are intended to assist in a further understanding of the invention. Particular materials employed, species and conditions are intended to be further illustrative of the invention and not limiting of the reasonable scope thereof.

Example 1 5-Chloro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate

A 60% dispersion of NaH in mineral oil (1.07 g, 26.9 mmol) was washed with hexane, and the resulting powder was suspended in 40 mL of DMF. After cooling the stirred mixture to 0° C., ethyl 5-chloro-1H-indole-2-carboxylate (5.00 g, 22.4 mmol) was added in portions. The solution was warmed to room temperature, during which gas was released. After 15 minutes, the mixture was cooled again to 0° C., and benzenesulfonyl chloride was added dropwise (3.14 mL, 24.6 mmol). After warming to room temperature, the reaction was stirred for 1.5 hours, then poured into a mixture of EtOAc and saturated aqueous NaHCO₃ solution. The organic phase was washed with water and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo. The resulting solid was stirred in 50 mL of a 10% EtOAc/hexane solution for 30 minutes, then filtered to provide the titled product as a white powder. Proton NMR for the product was consistent with the titled compound. ESI+MS: 364.1 [M+H]⁺.

Step B: 5-Chloro-2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonic Acid

To a solution of ethyl 5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate (5.56 g, 15.3 mmol) in 50 mL of dichloromethane at 0° C. was added acetic anhydride (7.23 mL, 76.6 mmol), followed by dropwise addition of concentrated sulfuric acid. The solution was warmed to room temperature, stirred for 3 hours, and partitioned between 0.5 L of EtOAc and 0.5 L of 3N HCl solution. The organic phase was washed with brine, dried with Na₂SO₄, filtered, and concentrated in vacuo. The product was reconcentrated from benzene in vacuo to give the titled product as a yellow solid. Proton NMR for the product was consistent with the titled compound of the formula C₁₇H₁₄ClNO₇S₂.0.5 CH₃CO₂H. ESI+MS: 444.0 [M+H]⁺, 466.0 [M+Na]⁺.

Step C: Ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

To a solution of the 5-chloro-2-(ethoxycarbonyl)-1-(phenylsulfonyl)-1H-indole-3-sulfonic acid (9.52 g, 21.4 mmol) in 100 mL of dichloromethane at 0° C. was added oxalyl chloride (5.61 mL, 64.3 mmol). Dimethylformamide (0.2 mL) was added, and the reaction was allowed to warm to room temperature. After 24 hours, another portion of oxalyl chloride (3.0 mL) was added, and the reaction was stirred for an additional 16 hours. The mixture was concentrated in vacuo to provide a yellow foam. Proton NMR for the product was consistent with the titled compound. ESI+MS: 426.2 [M-Cl]⁺.

Step D: Ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

To a solution of ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (149 mg, 0.322 mmol) in 5 mL of dichloromethane at 0° C. was added triethylamine (0.050 mL, 0.39 mmol), followed by morpholine (0.040 mL, 0.48 mmol). After four hours, the mixture was concentrated in vacuo to give the crude titled product. ESI+MS: 513.1 [M+H]⁺.

Step E: 5-chloro-3-[(methylamino)sulfonyl]-1H-indole-2-carboxamide

A sealed tube was charged with ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (ca. 0.32 mmol) and 5 mL of isopropanol. The solution was cooled in an ice bath, and ammonia gas was bubbled through the solution for 5 minutes. The tube was sealed, and heated at 100° C. for 18 hours. The mixture was concentrated in vacuo, taken up in 0.5 mL of 80% DMF/water solution, filtered, and purified by preparative reverse phase HPLC to afford the titled product. Proton NMR for the product was consistent with the titled compound. ESI+MS: 344.0 [M+H]⁺.

Example 2 5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with ethyl 5-bromo-1H-indole-2-carboxylate in Step A, the title compound was obtained. ESI+MS: 505.0 [M+H]⁺.

Step B: Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

To a solution of ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (10.9 mmol) in 150 mL of dichloromethane at 0° C. was added triethylamine (1.53 mL, 10.9 mmol), followed by morpholine (1.34 mL, 15.3 mmol). After 30 minutes, the mixture was poured into ethyl acetate and saturated NaHCO₃ solution, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo to give the titled product. ESI+MS: 557.0 [M+H]⁺.

Step C: Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

To a solution of ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (10.9 μmmol) in 75 mL of THF was added NaOH (482 mg, 12.0 mmol) dissolved in 2 mL of water. After one hour, the reaction was poured into ethyl acetate and water, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo to give the titled product, which was recrystallized from EtOAc/hexane. ESI+MS: 417.1 [M+H]⁺.

Step D: 5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained after crystallization from EtOAc/hexane.

¹H NMR (500 MHz, CD₃OD): δ 8.22 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 7.48 (dd, J=8.8, 1.7 Hz, 1H), 3.69 (m, 4H), 2.99 (m, 4H) ppm. ESI+MS: 388.0 [M+H]⁺.

Example 3 5-Iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 3,5-diiodo-1H-indole-2-carboxylate

Ethyl indole-2-carboxylate (5.00 g, 26.4 mmol), iodine (6.71 g, 26.4 mmol), sodium periodate (2.82 g, 13.2 mmol) and concentrated sulfuric acid (2.94 mL, 52.8 mmol) were combined in 50 mL of absolute ethanol and heated to reflux for 1.5 hours. The vessel was cooled to ambient temperature and poured into a biphasic mixture of ethyl acetate (100 mL) and saturated aqueous sodium sulfite (100 mL) solution. The organic layer was removed and the aqueous layer was further extracted twice with ethyl acetate. The combined organic extracts were washed once with aqueous saturated NaCl, dried with Na₂SO₄, filtered and concentrated in vacuo to provide the title product. ESI+MS: 441.8 [M+H]⁺.

Step B: Ethyl 5-iodo-1H-indole-2-carboxylate

Ethyl 3,5-diiodo-1H-indole-2-carboxylate (12.1 g, 26.4 mmol) was suspended in 250 mL of absolute ethanol, to which concentrated aqueous hydrogen chloride (22.0 mL, 264 mmol) was added. Zinc dust (17.3 g, 264 mmol) was added portionwise over 30 minutes. After stirring for 45 minutes, two additional portions of zinc were added slowly (5.2 and 4.4 g, 146 mmol). After stirring for 30 minutes, the mixture was poured into water and extracted four times with ethyl acetate. The combined organic extracts were washed once with aqueous saturated NaHCO₃ and once with aqueous saturated NaCl. The organic extract was dried with Na₂SO₄, filtered and concentrated in vacuo. The residue was crystallized three times from hexanes and ethyl acetate, providing the title compound. The mother liquor was columned by flash chromatography (0 to 8% ethyl acetate in hexanes) to provide an additional amount of the title compound. HRMS (ES) exact mass calculated for C₁₁H₁₀INO₂ (M+Na⁺): 377.9648. Found 377.9649.

Step C: Ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with ethyl 5-iodo-1H-indole-2-carboxylate in Step A, the title compound was obtained. ESI+MS: 518.07 [M-Cl]⁺.

Step D: 5-Iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 436.0 [M+H]⁺.

Example 4 5-Methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 3-(chlorosulfonyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with ethyl 5-methoxy-1H-indole-2-carboxylate in Step A, the title compound was obtained. ESI+MS: 408.0 [M-Cl]⁺.

Step B: 5-Methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. HRMS (ES) exact mass calculated for C₁₄H₁₈N₃O₅S (M+H⁺): 340.0962. Found 340.0960.

Example 5 6-Methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Methyl 3-(chlorosulfonyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with methyl 6-methoxy-1H-indole-2-carboxylate in Step A, the title compound was obtained. ESI+MS: 408.1 [M-Cl]⁺.

Step B: 6-Methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with methyl 3-(chlorosulfonyl)-6-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₄H₁₈N₃O₅S (M+H⁺): 340.0962. Found 340.0969.

Example 6 5-(Methylsulfonyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps A-E of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with methyl 5-(methylsulfonyl)-1H-indole-2-carboxylate in Step A, the title compound was obtained. HRMS (ES) exact mass calculated for C₁₄H₁₈N₃O₆S₂ (M+H⁺): 388.0632. Found 388.0649.

Example 7 7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 3-(chlorosulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with ethyl 7-nitro-1H-indole-2-carboxylate in Step A, the title compound was obtained.

Step B: 3-(Morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxamide

Following the procedures described in Steps B and C of Example 2 and E of Example 1, replacing in Step B of Example 2 ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and replacing in Step E of Example 1 ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxylate, the title compound was obtained. HRMS (ES) exact mass calculated for C₁₃H₁₅N₄O₆S (M+H⁺): 355.0707. Found 355.0713.

Step C: 7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a solution of 3-(morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxamide (708 mg, 2.00 mmol) in 30 mL of methanol was added 10% palladium on carbon (200 mg), and the reaction was equipped with a balloon of hydrogen gas. After 2 hours, the reaction was filtered through celite, the filter pad was rinsed with ethyl acetate, and the resulting solution was concentrated in vacuo to provide the titled compound as a yellow solid. A portion of this was taken up in dichloromethane, treated with excess ethereal HCl, and concentrated in vacuo to give an off-white solid, used for biological testing. HRMS (ES) exact mass calculated for C₁₃H₁₇N₄O₄S (M+H⁺): 325.0965. Found 325.0971.

Example 8 3-(Morpholin-4-ylsulfonyl)-5-nitro-1H-indole-2-carboxamide

Step A: Ethyl 3-(chlorosulfonyl)-5-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with ethyl 5-nitro-1H-indole-2-carboxylate in Step A, the title compound was obtained. ESI+MS: 437.2 [M-Cl]⁺.

Step B: 3-(Morpholin-4-ylsulfonyl)-5-nitro-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. ESI+MS: 355.1 [M+H]⁺.

Example 9 5-Chloro-3-(piperazin-1-ylsulfonyl)-1H-indole-2-carboxamide trifluoroacetate

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine with N-Boc-piperazine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₆ClN₄O₃S (M+H⁺): 343.0626. Found 343.0624.

Example 10 3-[(4-Benzylpiperazin-1-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine with N-benzylpiperazine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₂₀H₂₂ClN₄O₃S (M+H⁺): 433.1096. Found 433.1084.

Example 11 3-[(4-Acetylpiperazin-1-yl)sulfonyl]-5-chloro-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine with N-acetylpiperazine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₅H₁₈ClN₄O₄S (M+H⁺): 385.0732. Found 385.0722.

Example 12 5-Chloro-3-(piperidin-1-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine and triethylamine with piperidine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₄H₁₇ClN₃O₃S (M+H⁺): 342.0674. Found 342.0671.

Example 13 5-Chloro-3-(pyrrolidin-1-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine and triethylamine with pyrrolidine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₅ClN₃O₃S (M+H⁺): 328.0517. Found 328.0514.

Example 14 5-Chloro-3-(thiomorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine and triethylamine with thiomorpholine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₅ClN₃O₃S₂ (M+H⁺): 360.0238. Found 360.0248.

Example 15 3-(Azetidin-1-ylsulfonyl)-5-chloro-1H-indole-2-carboxamide

The titled compound was prepared using the procedures described in Steps B and C of Example 2, followed by the procedure described in Step E of Example 1, replacing in Step B of Example 2 ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine. Proton NMR for the product was consistent with the titled compound.

¹H NMR (500 MHz, CD₃OD): δ 8.07 (d, J=1.5 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.36 (dd, J=8.8, 2.2 Hz, 1H), 3.76 (t, J=7.7 Hz, 4H), 2.05 (hex, J=7.6 Hz, 2H) ppm. HRMS (ES) exact mass calculated for C₁₂H₁₃ClN₃O₃S (M+H⁺): 314.0361. Found 314.0342.

Example 16 5-Chloro-3-[(oxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide

Step A: Ethyl 5-chloro3-(thiomorpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

The titled compound was prepared using the procedures described in Steps B and C of Example 2, replacing in Step B ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with thiomorpholine. Proton NMR for the product was consistent with the titled compound. ESI+MS: 389.1 [M+H]⁺.

Step B: Ethyl 5-chloro-3-[(oxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxylate

To a solution of ethyl 5-chloro3-(thiomorpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (150 mg, 0.386 mmol) in 5 mL of dichloromethane was added meta-chloroperbenzoic acid (93 mg, 0.54 mmol). After 40 minutes, 1 mL of saturated NaHCO₃ solution was added, and the mixture was subjected to flash chromatography on silica gel (dichloromethane/EtOAc) to produce the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 405.1 [M+H]⁺.

Step C: 5-Chloro-3-[(oxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, ethyl 5-chloro-3-[(oxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxylate was converted to the title compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 376.1 [M+H]⁺.

Example 17 5-Chloro-3-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide

Step A: Ethyl 5-chloro-3-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxylate

To a solution of ethyl 5-chloro-3-(thiomorpholin-4-ylsulfonyl)-1H-indole-2-carboxylate from Example 16 (150 mg, 0.386 mmol) in 5 mL of dichloromethane was added meta-chloroperbenzoic acid (166 mg, 0.97 mmol). After 16 hours, the reaction was partitioned between dichloromethane and saturated NaHCO₃ solution. The aqueous phase was extracted with dichloromethane (3×), and the combined organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (dichloromethane/EtOAc) gave the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 421.1 [M+H]⁺.

Step B: 5-Chloro-3-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, ethyl 5-chloro-3-[(1,1-dioxidothiomorpholin-4-yl)sulfonyl]-1H-indole-2-carboxylate was converted to the title compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₈ClN₄O₅S₂ (M+NH₄ ⁺): 409.0402. Found 409.0410.

Example 18 cis-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl cis-5-chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

To a mixture of cis- and (±)-trans-2,6-dimethylmorpholine (0.36 mL, 2.9 mmol) in 20 mL of ethyl acetate at 0° C. was added 5 mL of saturated NaHCO₃ solution, followed by ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (970 mg, 2.10 mmol). After 30 minutes, the organic layer was dried (Na₂SO₄), filtered, and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexane) provided a product, which was purified further by preparative HPLC (DeltaPak C-18) to separate the titled cis-diastereomer from the corresponding trans-isomer. Proton NMR for the cis-diastereomer was consistent with the titled compound.

Step B: cis-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, ethyl cis-5-chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 372.1 [M+H]⁺.

Example 19 trans-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, Enantiomer A

Step A: (+)- and (−)-Ethyl trans-5-chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

The trans-isomer (ca. 120 mg) of the product from Step A of Example 18 was resolved by preparative chiral HPLC (ChiralPak AD) to produce a first-eluting enantiomer, and a second-eluting enantiomer. Proton NMR spectra for the two compounds were identical, and were consistent with the titled compounds.

Step B: trans-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, Enantiomer A

Following the procedure described in Step E of Example 1, the first-eluting enantiomer of ethyl trans-5-chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the title compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 372.1 [M+H]⁺.

Example 20 (trans-5-Chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, Enantiomer B

Using the same procedures described for Example 19, the second-eluting enantiomer of ethyl trans-5-chloro-3-(2,6-dimethylmorpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate from Step A of Example 19 was converted to the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 372.1 [M+H]⁺.

Example 21 5-Chloro-3-[(3-hydroxyazetidin-1-yl)sulfonyl]-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D morpholine with 3-hydroxyazetidine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 330.0 [M+H]⁺.

Example 22 (±)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Step A: Ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedure described in Step D of Example 1, replacing morpholine with (±)-2-(phenoxymethyl)morpholine (G. A. Showell et al., Bioorg. Med. Chem. Lett. 1998, 6, 1-8.), the title compound was obtained after purification by flash chromatography on silica gel (ethyl acetate/hexanes). Proton NMR for the product was consistent with the titled compound. ESI+MS: 619.2 [M+H]⁺.

Step B: (±)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the title compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 450.0 [M+H]⁺.

Example 23 (S)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Step A: Ethyl(S)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate

The product from Step A of Example 22 was resolved by preparative chiral HPLC (ChiralPak AD) to produce a first-eluting enantiomer and a second-eluting enantiomer. To assign the (S)-configuration to the first-eluting enantiomer, (S)-2-(phenoxymethyl)morpholine (from resolution of the racemate by preparative ChiralPak AD HPLC) was converted to the titled product using the procedure described in Step A of Example 22. The configuration of (S)-2-(phenoxymethyl)morpholine was assigned by ¹H NMR analysis of the derived Mosher's amide (cf. J. Org. Chem. 1996, 61, 2056-2064).

Step B: (S)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, ethyl(S)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the title compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 450.0 [M+H]⁺.

Example 24 (R)-5-Chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Using the same procedures described for Example 23, the second-eluting enantiomer of ethyl 5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate from Step A of Example 23 was converted to the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 449.9 [M+H]⁺.

Example 25 5-Bromo-3-({4-[2-(dimethylamino)ethyl]-5-oxo-1,4-diazepan-1-yl}sulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 4-[2-(dimethylamino)ethyl]-1,4-diazepan-5-one oxalate, the title compound was obtained as a white solid. HRMS (ES) exact mass calculated for C₁₈H₂₅BrN₅O₄S (M+H⁺): 486.0805. Found 486.0801.

Example 26 5-Bromo-3-({5-oxo-1,4-diazepan-1-yl}sulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 1,4-diazepan-5-one, the title compound was obtained. HRMS (ES) exact mass calculated for C₁₄H₁₅BrN₄O₄S (M+H⁺): 415.0070. Found 415.0072.

Example 27 5-Bromo-3-[(3-oxopiperazin-1-yl)sulfonyl]-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with piperazin-2-one trifluoroacetate, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 402.1 [M+H]⁺.

Example 28 5-Bromo-3-[(3-hydroxyazetidin-1-yl)sulfonyl]-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 3-hydroxyazetidine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 374.1 [M+H]⁺.

Example 29 (±)-5-Bromo-3-{[2-(aminocarbonyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with (±)-methyl morpholin-2-carboxylate (F. D. King, R. T. Martin, Tetrahedron Lett. 1991, 32, 2281), the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 431.1 [M+H]⁺.

Example 30 3-(Azetidin-1-ylsulfonyl)-5-bromo-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine, the title compound was obtained. HRMS (ES) exact mass calculated for C₁₂H₁₃BrN₃O₃S (M+H⁺): 357.9856. Found 357.9859.

Example 31 5-Bromo-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-bromo-3-{[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedure described in Step B of Example 2, replacing morpholine with N-Boc-piperazine, the title compound was obtained. The crude material was purified by flashchromatography on silica gel (35% EtOAc/hexane) to produce the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 656.0 [M+H]⁺.

Step B: Ethyl 5-bromo-1-(phenylsulfonyl)-3-(piperazin-1-ylsulfonyl)-1H-indole-2-carboxylate hydrochloride

Through a solution of ethyl 5-bromo-3-{[4-(tert-butoxycarbonyl)-piperazin-1-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate (44 mg, 0.067 mmol) in 5 mL of ethyl acetate at 0° C. was bubbled HCl gas for 2 minutes. After stirring an additional 30 minutes, the reaction was concentrated in vacuo to provide the titled product as a white solid. ESI+MS: 556.0 [M+H]⁺.

Step C: Ethyl 5-bromo-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate

To a solution ethyl 5-bromo-1-(phenylsulfonyl)-3-(piperazin-1-ylsulfonyl)-1H-indole-2-carboxylate hydrochloride (20 mg, 0.034 mmol) in 1.0 mL of dichloromethane at room temperature was added triethylamine (0.019 mL, 0.14 mmol), followed by 4-(methoxy)benzenesulfonyl chloride (8.0 mg, 0.041 mmol). After stirring overnight, the solvent was removed under a stream of nitrogen to provide the titled compound.

Step D: 5-Bromo-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide

Following the procedure described in Step E of Example 1, ethyl 5-bromo-3-({4-[(4-methoxyphenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound. ESI+MS: 557.0 [M+H]⁺.

Example 32 5-Bromo-3-({4-[(4-bromophenyl)sulfonyl]piperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps C and D of Example 31, replacing in Step C 4-(methoxy)benzenesulfonyl chloride with 4-bromobenzenesulfonyl chloride, the title compound was obtained after purification by preparative reversed phase HPLC. ESI+MS: 605.1 [M+H]⁺.

Example 33 5-Bromo-3-{[4-(3-morpholin-4-ylpropyl)-3-oxopiperazin-1-yl]sulfonyl}-1H-indole-2-carboxamide

Step A: tert-Butyl 4-but-3-enyl-3-oxopiperazine-1-carboxylate

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.500 mg, 2.50 mmol) in 10 μL of DMF at 0° C. was added NaH as a 60% dispersion in mineral oil (2.62 mmol), and the reaction was stirred for 45 minutes. 4-Bromo-1-butene was added (0.280 mL, 2.75 mmol) dropwise as a solution in 1 mL of THF. The solution was stirred overnight, allowing it to warm to room temperature. The reaction was partitioned between EtOAc and saturated NaHCO₃ solution. The organic phase was washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to give the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 255.1 [M+H]⁺.

Step B: tert-Butyl 3-oxo-4-(3-oxopropyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-but-3-enyl-3-oxopiperazine-1-carboxylate (0.246 mg, 0.97 mmol) in 10 mL of 1:1 acetone:water was added sodium metaperiodate (621 mg, 2.90 mmol), followed by a solution of 0.25 M aqueous osmium tetraoxide (0.192 mL, 0.048 mmol). After stirring overnight, the reaction was partitioned between EtOAc and brine. The organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo to give the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 257.3 [M+H]⁺.

Step C: tert-Butyl 4-(3-morpholin-4-ylpropyl)-3-oxopiperazine-1-carboxylate

To a solution of tert-butyl 3-oxo-4-(3-oxopropyl)piperazine-1-carboxylate (0.45.0 mg, 0.176 mmol) in 2 mL of 1,2-dichloroethane was added morpholine (0.017 mL, 0.19 mmol), sodium triacetoxyborohydride (56 mg, 0.26 mmol), acetic acid (0.050 mL, 0.88 mmol), and powdered 4 angstrom molecular sieves (ca. 100 mg). After 4 hours, the reaction was partitioned between EtOAc and 10% citric acid solution. The organic phase was washed with saturated NaHCO₃ solution and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to give the titled compound as a dark oil. Proton NMR for the product was consistent with the titled compound. ESI+MS: 328.4 [M+H]⁺.

Step D: 1-(3-Morpholin-4-ylpropyl)piperazin-2-one Hydrochloride

Through a solution of tert-butyl 4-(3-morpholin-4-ylpropyl)-3-oxopiperazine-1-carboxylate (45 mg, 0.14 mmol) in 5 mL of ethyl acetate at 0° C. was bubbled HCl gas for 2 minutes. After stirring an additional 30 minutes, the reaction was concentrated in vacuo to provide the titled product. ESI+MS: 228.4 [M+H]⁺.

Step E: 5-Bromo-3-{[4-(3-morpholin-4-ylpropyl)-3-oxopiperazin-1-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 1-(3-morpholin-4-ylpropyl)piperazin-2-one hydrochloride, the title compound was obtained. ESI+MS: 528.3 [M+H]⁺.

Example 34 5-Bromo-3-({4-[3-(dimethylamino)propyl]-3-oxopiperazin-1-yl}sulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps C, D and E of Example 33, replacing in Step C morpholine and acetic acid with dimethylamine hydrochloride, the title compound was obtained after purification by preparative reversed phase HPLC. ESI+MS: 486.3 [M+H]⁺.

Example 35 5-Bromo-3-(2,5-dihydroxy-1H-pyrrol-1-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 2,5-dihydro-1H-pyrrole, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 370.13 [M+H]⁺.

Example 36 cis-5-Bromo-3-(6-oxa-3-azabicyclo[3.1.0]hex-3-ylsulfonyl)-1H-indole-2-carboxamide

To a stirring suspension of 5-bromo-3-(2,5-dihydroxy-1H-pyrrol-1-ylsulfonyl)-1H-indole-2-carboxamide (10 mg, 0.027 mmol, 1.0 equiv.) in 2 mL of acetone was added m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.). After stirring for 3 hours, 3 mL of tetrahydrofuran and m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.) were added. After stirring an additional 72 hours, more m-chloroperoxybenzoic acid (13 mg, 0.076 mmol, 2.8 equiv.) was added and, after 3 hours, the solvent was removed in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 385.96 [M+H]⁺.

Example 37 (±)-5-Bromo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with (±)-2-(phenoxymethyl)morpholine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 493.91 [M+H]⁺.

Example 38 (S)-5-Bromo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps A and B of Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 493.95 [M+H]⁺.

Example 39 (R)-5-Bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Using the same procedures described for Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the second-eluting enantiomer of ethyl 5-bromo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 493.85 [M+H]⁺.

Example 40 6-Hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a suspension of 6-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 5 (134 mg, 0.395 mmol) in 5 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 1.97 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 4 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO₃ solution. The organic phase was washed with water and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo. Trituration with chloroform gave the titled compound as a brown powder. HRMS (ES) exact mass calculated for C₁₃H₁₆N₃O₅S (M+H⁺): 326.0805. Found 326.0794.

Example 41 3-(Morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (96 mg, 0.25 mmol) was dissolved in 7 mL of a 1:1 mixture of EtOH:EtOAc. The vessel was degassed and charged with 10% palladium on carbon (15 mg, 15 weight percent).

The vessel was then charged with 1 atm. H₂ and stirred vigorously for 18 hours. The reaction was filtered through a pad of Celite, the pad was washed with a solution of EtOH:EtOAc (1:1) and the filtrate was concentrated in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₆N₃O₄S (M+H⁺): 310.0856. Found 310.0866.

Example 42 5-(2-Furyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (50 mg, 0.13 mmol, 1.0 equiv), 2-(tributylstannyl)furan (48 μL, 0.15 mmol, 1.2 equiv), tri-o-tolylphosphine (7.8 mg, 0.03 mmol, 0.2 equiv) and palladium(II)acetate (2.9 mg, 0.015 mmol, 0.1 equiv) were dissolved in 5 mL of dry DMF and heated to 90° C. for 1 hour. The mixture was cooled to ambient temperature, poured into aqueous saturated NaHCO₃ and the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by flash chromatography through silica gel (0-5% MeOH with 10% NH₄OH/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 376.1 [M+H]⁺.

Example 43 3-(Morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide

Using the procedure described in Example 42, replacing 2-(tributylstannyl)furan with tributyl(phenylethynyl)stannane, provided the crude title compound, which was triturated from hexanes and ethyl acetate to provide pure product. Proton NMR was consistent with the titled compound. HRMS (ES) exact mass calculated for C₂₁H₂₀N₃O₄S (M+H⁺): 410.1169. Found 410.1144.

Example 44 3-(Morpholin-4-ylsulfonyl)-5-(2-phenylethyl)-1H-indole-2-carboxamide

3-(Morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide (50 mg, 0.12 mmol, 1.0 equiv) was dissolved in 10 mL of methanol. The vessel was degassed and charged with 10% palladium on carbon (5 mg, 10 weight percent). The vessel was then charged with 1 atm. H₂ and stirred vigorously for 1 hour. The reaction was filtered through a pad of Celite, the pad was washed with methanol and the filtrate was concentrated in vacuo to provide the title compound. Proton NMR was consistent with the titled compound. HRMS (ES) exact mass calculated for C₂₁H₂₄N₃O₄S (M+H⁺): 414.1482. Found 414.1479.

Example 45 5-Hex-1-ynyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 43, replacing tributyl(phenylethynyl)stannane with tributyl(hex-1-ynyl)stannane, the title compound was obtained. Proton NMR was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₉H₂₄N₃O₄S (M+H⁺): 390.1482. Found 390.1456.

Example 46 5-Hexyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 44, replacing 3-(morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide with 5-hex-1-ynyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, the title compound was obtained Proton NMR was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₉H₂₈N₃O₄S (M+H⁺): 394.1795. Found 394.1793.

Example 47 5-Bromo-6-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-bromo-6-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

Ethyl 5-bromo-6-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (256 mg, 0.55 mmol, 1.0 equiv) was suspended in 10 mL of absolute ethanol. 1.5 mL of concentrated aqueous HCl was added, followed Zn dust (362 mg, 5.5 mmol, 10 equiv), and the reaction was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water, which was extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ¹H NMR (500 MHz, DMSO-d₆): δ 12.38 (s, 1H), 8.15 (br s, 1H), 8.05 (br s, 1H), 7.91 (s, 1H), 6.94 (s, 1H), 3.62 (m, 4H), 2.87 (m, 4H) ppm. ESI+MS: 431.2 [M+H]⁺.

Step B: 5-Bromo-6-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-6-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 403.2 [M+H]⁺.

Example 48 Methyl 2-(aminocarbonyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-5-carboxylate

5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (200 mg, 0.515 mmol, 1.0 equiv), palladium(II)acetate (50 mg, 0.051 mmol, 0.1 equiv) and [3-(diphenylphosphino)propyl](diphenyl)phosphine (dppp) (21 mg, 0.051 mmol, 0.1 equiv) were dissolved in 10 mL of 1:1 solution of DMSO:MeOH. The vessel was placed under 1 atm of CO and heated to 70° C. for 18 hours. To the reaction mixture was added palladium(II)acetate (50 mg, 0.051 mmol, 0.1 equiv) and tri-o-tolylphosphine (31 mg, 0.10 mmol, 0.2 equiv) and the vessel was again placed under 1 atm of CO and heated to 70° C. for an additional 18 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 368.1 [M+H]⁺.

Example 49 3-(Morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide

5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), palladium(II)acetate (12 mg, 0.012 mmol, 0.1 equiv), tri-o-tolylphosphine (31 mg, 0.100 mmol, 0.2 equiv) and triethylamine (150 μL, 1.03 mmol, 2.0 equiv) were dissolved in 5 mL of DMF, the vessel was charged with 1 atm of ethylene and heated to 100° C. for 24 hours. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₅H₁₈N₃O₄S (M+H⁺): 336.1013. Found 336.1016.

Example 50 5-Hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a suspension of 5-methoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 4 (416 mg, 1.23 mmol) in 15 mL of dichloromethane at −78° C. was added boron tribromide solution (1 M in dichloromethane, 6.13 mmol). After 10 minutes the mixture was allowed to warm to room temperature, and stir for an additional 60 hours. The reaction was poured into a mixture of EtOAc and saturated aqueous NaHCO₃ solution. The organic phase was washed with water and brine, dried with Na₂SO₄, filtered, and concentrated in vacuo. Purification by flash chromatography through silica gel (3-10% MeOH/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₆N₃O₅S (M+H⁺): 326.0805. Found 326.0808.

Example 51 5-Ethoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (32 mg, 0.098 mmol) in 1 mL of dimethylformamide was added cesium carbonate (95 mg, 0.29 mmol) and iodoethane (0.0094 mL, 0.12 mmol). After one hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₅H₂₀N₃O₅S (M+H⁺): 354.1118. Found 354.1094.

Example 52 3-(Morpholin-4-ylsulfonyl)-5-propoxy-1H-indole-2-carboxamide

To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (29 mg, 0.089 mmol) in 1 mL of dimethylformamide was added cesium carbonate (86 mg, 0.27 mmol) and 1-iodopropane (0.0094 mL, 0.096 mmol). After one hour, another portion (0.005 mL) of 1-iodopropane was added. After an additional hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. HRMS (ES) exact mass calculated for C₁₆H₂₂N₃O₅S (M+H⁺): 368.1275. Found 368.1291.

Example 53 5-Isopropoxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (26 mg, 0.079 mmol) in 1 mL of dimethylformamide was added cesium carbonate (77 mg, 0.24 mmol) and 2-iodopropane (0.0091 mL, 0.095 mmol). After 24 hours, another portion (0.009 mL) of 2-iodopropane was added. After three days, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. ESI+MS: 368.2 [M+H]⁺.

Example 54 5-Ethyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 44, replacing 3-(morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide with 3-(morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide, the title compound was obtained. Proton NMR was consistent with the titled compound. ESI+MS: 338.1 [M+H]⁺.

Example 55 2-(Aminocarbonyl)-3-(morpholin-4-ylsulfonyl)-1H-indol-5-yl Methanesulfonate

To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (37 mg, 0.12 mmol) in 3 mL of dichloromethane/acetonitrile (1:1) was added triethylamine (0.048 mL, 0.34 mmol) and methanesulfonyl chloride (0.0098 mL, 0.13 mmol). After one hour, another portion of methanesulfonyl chloride (0.005 mL) was added. After another 10 minutes, the mixture was partitioned between ethyl acetate and saturated NH₄Cl solution, and the organic layer was washed with saturated NaHCO₃ solution and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting solid was triturated with acetonitrile/methanol (1:1) to give the titled compound as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₄H₁₈N₃O₇S₂ (M+H⁺): 404.0581. Found 404.0620.

Example 56 3-(Morpholin-4-ylsulfonyl)-5-prop-1-ynyl-1H-indole-2-carboxamide

Using the procedure described in Example 43, replacing tributyl(phenylethynyl)stannane with tributyl(prop-1-ynyl)stannane, the title compound was obtained. Proton NMR was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₆H₁₈N₃O₄S (M+H⁺): 348.1013. Found 338.1013.

Example 57 3-(Morpholin-4-ylsulfonyl)-5-thien-2-yl-1H-indole-2-carboxamide

Using the procedure described in Example 43, replacing tributyl(phenylethynyl)stannane with tributyl(thien-2-yl)stannane, the title compound was obtained. Proton NMR was consistent with the titled compound. ESI+MS: 392.1 [M+H]⁺.

Example 58 3-(Azetidin-1-ylsulfonyl)-5-methoxy-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine, the title compound was obtained. HRMS (ES) exact mass calculated for C₁₃H₁₆N₃O₄S (M+H⁺): 310.0856. Found 310.0877.

Example 59 5-Formyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

3-(Morpholin-4-ylsulfonyl)-5-vinyl-1H-indole-2-carboxamide (207 mg, 0.617 mmol, 1.0 equiv), sodium periodate (660 mg, 3.09 mmol, 5.0 equiv) and osmium tetraoxide (16 mg, 0.062 mmol, 0.1 equiv) were dissolved in 18 mL of a 5:1 solution of acetone:water and stirred for 18 hours. The mixture was poured into aqueous saturated NaHCO₃ and extracted three times with dichloromethane. The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 338.1 [M+H]⁺.

Example 60 5-Methyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (106 mg, 0.273 mmol, 1.0 equiv), dichlorobis(triphenylphosphine)palladium(II) (50 mg, 0.07 mmol, 0.15 equiv) and tetramethyltin (270 μL, 1.91 mmol, 4.0 equiv) were combined in 5 mL of a 1:1 solution of DMF:HMPA. The solution was degassed and heated to 120° C. for 24 hours.

The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₄H₁₈N₃O₄S (M+H⁺): 324.1013. Found 324.1014.

Example 61 7-(Acetylamino)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (52 mg, 0.16 mmol) in 1 mL of dichloromethane at 0° C. was added triethylamine (0.067 mL, 0.91 mmol) and acetic anhydride (0.058 mL, 0.52 mmol). After two hours, the mixture was partitioned between ethyl acetate and 3N HCl solution, and the organic layer was washed with saturated NaHCO₃ solution and brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to provide the titled compound. HRMS (ES) exact mass calculated for C₁₅H₁₈N₄O₅SNa (M+Na⁺): 389.0890. Found 389.0889.

Example 62 7-[(Methylsulfonyl)amino]-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (52 mg, 0.16 mmol) in 1 mL of dichloromethane at 0° C. was added triethylamine (0.067 mL, 0.91 mmol) and methanesulfonic anhydride (30 mg, 0.17 mmol). After one hour, another portion methanesulfonic anhydride was added, and after two hours, additional portions of methanesulfonic anhydride and triethylamine were added. After stirring overnight, 1 mL of 1N NaOH was added, and after an additional hour the mixture was partitioned between ethyl acetate and saturated NaHCO₃ solution. The organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. HRMS (ES) exact mass calculated for C₁₄H₁₉N₄O₆S₂ (M+H⁺): 403.0740. Found 403.0739.

Example 63 5-{[(4-methoxyphenyl)amino]methyl}-3-morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide

5-Formyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (41 mg, 0.12 mmol, 1.0 equiv), acetic acid (20 μL, 0.37 mmol, 2.0 equiv) and p-methoxyaniline (16 mg, 0.13 mmol, 1.1 equiv) were combined in 3 mL of methanol and stirred for 20 minutes. To the solution was added Na(CN)BH₃ (180 μL, 1.0M solution in THF, 0.18 mmol, 1.5 equiv) and the reaction was allowed to stir for 18 hours. The solvent was removed in vacuo and purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 445.3 [M+H]⁺.

Example 64 5-{[(2-acetamide)amino]methyl}-3-morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedure described in Example 63, replacing p-methoxyaniline with glycinamide hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 396.3 [M+H]⁺.

Example 65 3-(Morpholino-4-ylsulfonyl)-5-phenyl-1H-indole-2-carboxamide

Step A: tert-Butyl-5-bromo-2-{[(tert-butoxycarbonyl)amino]carbonyl}-3-(morpholin-4-ylsulfonyl)-1H-indole-1-carboxylate

5-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (612 mg, 1.58 mmol, 1.0 equiv) was dissolved in 10 mL of dry dimethylformamide and cooled to 0° C. Sodium hydride (189 mg, 60% dispersion in mineral oil, 4.73 mmol, 3.0 equiv) was added and the reaction was stirred for 30 minutes at 0° C. Di-tert-butyl dicarbonate (860 mg, 3.94 mmol, 2.5 equiv) was added and the reaction was warmed to ambient temperature overnight. After 18 hours, the reaction mixture was cooled to 0° C. and sodium hydride (189 mg, 60% dispersion in mineral oil, 4.73 mmol, 3.0 equiv) was added. After stirring for 30 minutes at 0° C., di-tert-butyl dicarbonate (860 mg, 3.94 mmol, 2.5 equiv) was added and the reaction was warmed to ambient temperature and stirred for 4 hours. The reaction was poured into aqueous saturated NaHCO₃ and extracted three times with dichloromethane. The combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo. The title compound was obtained after purification by flash chromatography on silica gel (ethyl acetate/hexanes). Proton NMR for the product was consistent with the titled compound. ESI+MS: 588.2 [M+H]⁺.

Step B: 3-(Morpholino-4-ylsulfonyl)-5-phenyl-1H-indole-2-carboxamide

tert-Butyl-5-bromo-2-{[(tert-butoxycarbonyl)amino]carbonyl}-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (75 mg, 0.13 mmol, 1.0 equiv), phenylboronic acid (17 mg, 0.14 mmol, 1.1 equiv), potassium carbonate (135 mg, 0.64 mmol, 5.0 equiv), palladium(II)acetate (1.4 mg, 0.0006 mmol, 0.05 equiv) and tri-o-tolylphosphine (3.9 mg, 0.013 mmol, 0.1 equiv) were combined in 5 mL of dimethylformamide and heated to 80° C. for 18 hours. The reaction was cooled to ambient temperature, poured into aqueous saturated NaHCO₃ and extracted three times with ethyl acetate. The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was taken up in 10 mL of ethyl acetate, cooled to 0° C. and the solution was saturated with HCl (g). After 30 minutes, the solvent was removed in vacuo and purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 386.3 [M+H]⁺.

Example 66 3-(Morpholino-4-ylsulfonyl)-5-pyrazin-2-yl-1H-indole-2-carboxamide

Step A: 1-tert-Butyl-2-ethyl 5-iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-1,2-dicarboxylate

Ethyl 5-iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (890 mg, 1.92 mmol, 1.0 equiv) was dissolved in 25 mL of dry dimethylformamide and cooled to 0° C. Sodium hydride (100 mg, 60% dispersion in mineral oil, 2.49 mmol, 1.3 equiv) was added and the reaction was stirred for 30 minutes at 0° C. Di-tert-butyl dicarbonate (439 mg, 2.01 mmol, 1.05 equiv) was added and the reaction was warmed to ambient temperature overnight. After 18 hours, the reaction was poured into aqueous saturated NaHCO₃ and extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered and concentrated in vacuo to provide the title compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 565.3 [M+H]⁺.

Step B: Ethyl 3-(morpholin-4-ylsulfonyl)-5-pyrazin-2-yl-1H-indole-2-carboxylate

1-tert-Butyl-2-ethyl 5-iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-1,2-dicarboxylate (100 mg, 0.18 mmol, 1.0 equiv), 2-(tributylstannyl)pyrazine (91 mg, 0.25 mmol, 1.4 equiv), tri-o-tolylphosphine (11 mg, 0.04 mmol, 0.2 equiv) and palladium(II)acetate (4.0 mg, 0.02 mmol, 0.1 equiv) were dissolved in 2 mL of dry DMF and heated to 120° C. for 18 hours. The mixture was cooled to ambient temperature, poured into aqueous saturated NaHCO₃ and the aqueous layer was extracted 3 times with dichloromethane. The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo. Purification by flash chromatography through silica gel (ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 417.4 [M+H]⁺.

Step C: 3-(Morpholino-4-ylsulfonyl)-5-pyrazin-2-yl-1H-indole-2-carboxamide

Following the procedure used in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(morpholin-4-ylsulfonyl)-5-pyrazin-2-yl-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 388.3 [M+H]⁺.

Example 67 3-(Morpholino-4-ylsulfonyl)-5-pyridin-2-yl-1H-indole-2-carboxamide

Following the procedures used in Example 66, replacing in Step B 2-(tributylstannyl)pyrazine2-(tributylstannyl)pyrazine with 2-(tributylstannyl)pyridine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 387.4 [M+H]⁺.

Example 68 3-(Morpholino-4-ylsulfonyl)-5-pyridin-4-yl-1H-indole-2-carboxamide

Following the procedures used in Example 66, replacing in Step B 2-(tributylstannyl)pyrazine with 4-(tributylstannyl)pyridine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 387.4 [M+H]⁺.

Example 69 5-(1-benzofuran-2-yl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-(1-benzofuran-2-yl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

1-tert-Butyl-2-ethyl 5-iodo-3-(morpholin-4-ylsulfonyl)-1H-indole-1,2-dicarboxylate (54 mg, 0.096 mmol, 1.0 equiv), 1-benzofuran-2-ylboronic acid (22 mg, 0.13 mmol, 1.4 equiv), tri-t-butylphosphine (3.9 mg, 0.02 mmol, 0.2 equiv) and palladium(II)acetate (2.1 mg, 0.01 mmol, 0.1 equiv) and cesium fluoride (73 mg, 0.48 mmol, 5.0 equiv) were dissolved in 5 μL of dry DME and heated to 90° C. for 3 hours. The mixture was cooled to ambient temperature, poured into aqueous saturated NaHCO₃ and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were dried (Na₂SO₄), filtered and concentrated in vacuo to provide the titled compound. ESI+MS: 455.1 [M+H]⁺.

Step B: 5-(1-benzofuran-2-yl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedure used in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-(1-benzofuran-2-yl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 426.1 [M+H]⁺.

Example 70 5-(5-Methyl-2-furyl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with 5-methyl-2-furylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 419.3 [M+H]⁺.

Example 71 5-(3,5-Dimethylisoxazole-4-yl)-3-(morpholino-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with 3,5-dimethylisoxazol-4-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 405.3 [M+H]⁺.

Example 72 3-(Morpholin-4-ylsulfonyl)-5-(1H-pyrrol-2-yl)-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with 1 (tert-butoxycarbonyl)1H-pyrrol-2-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 375.3 [M+H]⁺.

Example 73 3-(Morpholin-4-ylsulfonyl)-5-pyridin-3-yl-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with pyridin-3-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 387.3 [M+H]⁺.

Example 74 3-(Morpholin-4-ylsulfonyl)-5-(1,3-thiazol-2-yl)-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with 1,3-thiazol-2-ylboronic acid, the title compound was obtained. ¹H NMR (500 MHz, DMSO-d₆): δ 13.05 (s, 1H), 8.55 (s, 1H), 8.28 (br s, 1H), 8.21 (br s, 1H), 7.95 (dd, J=8.5, 1.5 Hz, 1H), 7.92 (d, J=3.4 Hz, 1H), 7.76 (d, J=3.18 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 3.63 (m, 4H), 2.95 (m, 4H) ppm. ESI+MS: 393.3 [M+H]⁺.

Example 75 3-(Morpholin-4-ylsulfonyl)-5-thien-3-yl-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with thien-3-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 392.3 [M+H]⁺.

Example 76 5-(1-Benzothien-3-yl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedures used in Example 69, replacing in Step A 1-benzofuran-2-ylboronic acid with 1-benzothien-3-ylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 442.3 [M+H]⁺.

Example 77 3-(Azetidin-1-yl}sulfonyl)-5-iodo-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with azetidine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 406.15 [M+H]⁺.

Example 78 3-[(3-Hydroxyazetidin-1-yl)sulfonyl]-5-iodo-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with 3-hydroxyazetidine, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 421.88 [M+H]⁺.

Example 79

(±)-5-Iodo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-iodo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with (±)-2-(phenoxymethyl)morpholine, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 541.89 [M+H]⁺.

Example 80 (S)-5-Iodo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps A and B of Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained after purification by preparative reversed phase HPLC. ¹H NMR (500 MHz, DMSO-d₆): δ 13.00 (br s, 1H), 8.27 (s, 1H), 8.25 (br s, 1H), 8.20 (br s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.27 (m, 2H), 6.94 (t, J=7.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 4.00-3.97 (m, 1H), 3.97-3.90 (m, 2H), 3.82 (m, 1H), 3.70 (br d, J=12.0 Hz, 1H), 3.56 (br t, J=11.6 Hz, 1H), 3.51 (br d, J=11.7 Hz, 1H), 2.47 (m, 1H), 2.39 (m, 1H) ppm. ESI+MS: 541.82 [M+H]⁺.

Example 81 (R)-5-Iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Using the same procedures described for Example 23, replacing the product from Step A of Example 22, ethyl(±)-5-chloro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, with ethyl(±)-5-iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate, the second-eluting enantiomer of ethyl 5-iodo-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1-(phenylsulfonyl)-1H-indole-2-carboxylate was converted to the titled compound after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 542.82 [M+H]⁺.

Example 82 7-Amino-6-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (109 mg, 0.336 mmol) in 5 mL of acetic acid was added a 3.3 M stock solution of bromine in acetic acid (0.12 mL, 0.40 mmol). After 30 minutes, the mixture was partitioned between ethyl acetate and saturated NaHCO₃ solution. The organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₆BrN₄O₄S (M+H⁺): 403.0070. Found 403.0069.

Example 83 7-Amino-4,6-dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

The titled compound was isolated from preparative reversed phase HPLC of the crude reaction mixture from Example 82. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₁₃H₁₅Br₂N₄O₄S (M+H⁺): 480.9175. Found 480.9177.

Example 84 6-Bromo-7-(dimethylamino)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Following the procedure used in Example 63, replacing 5-formyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide with formaldehyde and replacing p-methoxyaniline with 7-amino-6-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 431.2 [M+H]⁺.

Example 85 3-(Morpholin-4-ylsulfonyl)-7-[(pyridin-4-ylmethyl)amino]-1H-indole-2-carboxamide

To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (36 mg, 0.11 mmol) in 1 mL of methanol was added 4-formylpyridine (24 mg, 0.22 mmol). After stirring overnight, sodium borohydride was added (13 mg, 0.33 mmol). After 2 hours, the reaction was quenched with 3N HCl, concentrated in vacuo, taken up in DMF, and purified by preparative reversed phase HPLC. The titled product was obtained as a yellow solid. Proton NMR for the product was consistent with the titled compound. ESI+MS: 416.4 [M+H]⁺.

Example 86 7-{[(2-Chloropyridin-4-yl)methyl]amino}-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the method described in Example 85, replacing 4-formylpyridine with 3-chloro-4-formylpyridine, the titled product was obtained as a yellow solid (57% yield). Proton NMR for the product was consistent with the titled compound. ¹H NMR (500 MHz, DMSO-d₆): δ 12.50 (s, 1H), 8.36 (m, 2H), 8.21 (br s, 1H), 7.53 (s, 1H), 7.44 (d, J=5.1 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 6.99 (dd, J=8, 8 Hz, 1H), 6.86 (br s, 1H), 6.30 (d, J=7.6 Hz, 1H), 4.53 (s, 2H), 3.61 (m, 4H), 2.89 (s, 4H) ppm. HRMS (ES) exact mass calculated for C₁₉H₂₁ClN₅O₄S (M+H⁺): 450.0997. Found 450.0977.

Example 87 7-Nitro-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Step A: 7-Nitro-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxylic Acid

Following the procedure described in Steps B and C of Example 2, replacing in Step B ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate and replacing morpholine with (S)-2-(phenoxymethyl)morpholine from Step A of Example 23, the title compound was obtained. ESI+MS: 461.9 [M+H]⁺.

Step B: 7-Nitro-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

To a solution of 7-nitro-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxylic acid (330 mg, 0.715 mmol) in 3 mL of dichloromethane at room temperature was added oxalyl chloride (0.12 mL), followed by DMF (ca. 0.020 mL). After 20 minutes, the mixture was concentrated in vacuo. This was taken up in 3 mL of acetone, and a solution of 10% NH₄OH/acetone (6 mL) was added, whereupon a yellow precipitate formed. After 15 minutes, the reaction was concentrated in vacuo. Purification by flash chromatography on silica gel (2% MeOH/dichloromethane) provided the titled compound as a fluffy yellow solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₂₀H₂₁N₄O₇S (M+H⁺): 461.1126.

Found 461.1129.

Example 88 7-Amino-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Using the method described in Step C of Example 7,7-nitro-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide was converted to the titled product. Proton NMR for the product was consistent with the titled compound. ¹H NMR (500 MHz, CDCl₃): δ 9.34 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.28 (d, J=7.6 Hz, 2H), 7.10 (t, J=8.0 Hz, 1H), 6.97 (t, J=7.5 Hz, 1H), 6.85 (d, J=7.8 Hz, 2H), 6.60 (d, J=7.6 Hz, 1H), 6.19 (br s, 1H), 4.45 (m, 2H), 3.91-4.00 (m, 3H), 3.79-3.86 (m, 2H), 3.71 (dt, J=2.4, 11.5 Hz, 1H), 3.58 br d, J=11.2 Hz, 1H), 2.55 (dt, J=3.4, 11.9 Hz, 1H), 2.43 (t, J=10.5 Hz, 1H) ppm. HRMS (ES) exact mass calculated for C₂₀H₂₃N₄O₅S (M+H⁺): 431.1384. Found 431.1385.

Example 89 3-{[(2S)-2-(Phenoxymethyl)morpholin-4-yl]sulfonyl}-7-[(pyridin-4-ylmethyl)amino]-1H-indole-2-carboxamide

Using the method described in Example 85, 7-Amino-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide was converted to the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₂₆H₂₈N₅O₅S (M+H⁺): 522.1806. Found 522.1808.

Example 90 7-(Benzylamino)-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

Using the method described in Example 85, replacing 4-formylpyridine with benzaldehyde, 7-Amino-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide was converted to the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C₂₇H₂₉N₄O₅S (M+H⁺): 521.1853. Found 521.1856.

Example 91 7-Chloro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a stirring suspension of CuCl₂ (14 mg, 0.11 mmol, 2.5 equiv) and tert-butyl nitrite (9 mg, 0.09 mmol, 2.0 equiv) in 3 mL of acetonitrile was added a 2 mL acetonitrile solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (14 mg, 0.043 mmol, 1.0 equiv). After stirring for 72 hours, the solvent was removed in vacuo and the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 344.2 [M+H]⁺.

Example 92 6-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

6-Bromo-7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (25 mg, 0.062 mmol, 1.0 equiv) was dissolved in 5 mL of tetrahydrofuran and cooled to 0° C. 1.3 mL of hypophosphorous acid (50% weight in water) was added, immediately followed by Cu₂O (0.9 mg, 0.01 mmol, 0.1 equiv) and NaNO₂ (21.4 mg, 0.31 mmol), and the reaction was stirred for 90 minutes. The reaction mixture was partitioned between dichloromethane and water and extracted four times with dichloromethane. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 388.1 [M+H]⁺.

Example 93 7-Bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (26 mg, 0.080 mmol, 1.0 equiv) was dissolved in 2 mL of a 1:1 solution of tetrahydrofuran:water to which 0.2 mL of concentrated aqueous HBr was added and the mixture was cooled to 0° C. NaNO₂ (28 mg, 0.40 mmol, 5.0 equiv) was added in one portion, followed by CuBr (57 mg, 0.40 mmol, 5.0 equiv) 25 minutes later. The reaction was warmed to ambient temperature and stirred for 72 hours. The reaction mixture was partitioned between dichloromethane and water and extracted three times with dichloromethane. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 388.1 [M+H]⁺.

Example 94 7-Cyano-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

To a stirring suspension of CuCN (35 mg, 0.39 mmol, 1.25 equiv) and 7-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (100 mg, 0.31 mmol, 1.0 equiv) in 3 mL of DMSO was added dropwise tert-butyl nitrite (110 μL, 0.92 mmol, 3.0 equiv). After stirring for 18 hours, the title compound was obtained by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 335.3 [M+H]⁺.

Example 95 (±)-7-(Methylsulfinyl)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 94, the title compound was isolated as a side product by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 372.3 [M+H]⁺.

Example 96 7-Aminomethyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

7-Cyano-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (8 mg, 0.024 mmol) was dissolved in 5 mL of methanol. The vessel was degassed and charged with 10% Pd(OH)₂ on carbon (0.4 mg, 5 weight percent). The vessel was then charged with 1 atm. H₂ and stirred vigorously for 18 hours. The reaction was filtered through a pad of Celite, the pad was washed with methanol and the filtrate was concentrated in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 339.3 [M+H]⁺.

Example 97 5-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 44, replacing 3-(morpholin-4-ylsulfonyl)-5-(phenylethynyl)-1H-indole-2-carboxamide with 5-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 325.2 [M+H]⁺.

Example 98 (S)-5-Fluoro-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

Step A: Ethyl 3-(chlorosulfonyl)-5-fluoro-1-(phenylsulfonyl)-1H-indole-2-carboxylate

Following the procedures described in Steps A-C of Example 1, replacing ethyl 5-chloro-1H-indole-2-carboxylate with ethyl 5-fluoro-1H-indole-2-carboxylate in Step A, the title compound was obtained. ESI+MS: 432 [M+H]⁺.

Step B: (S)-5-Fluoro-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-fluoro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with (S)-2-(phenoxymethyl)morpholine from Step A of Example 23, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 433.9 [M+H]⁺.

Example 99 (R)-5-Fluoro-3-{[2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide

The titled compound was prepared using the same method described for Example 98, except that (R)-2-(phenoxymethyl)morpholine was used instead of (S)-2-(phenoxymethyl)morpholine. ESI+MS: 434.0 [M+H]⁺.

Example 100 5-Acetylamino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

5-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide trifluoroacetate salt (22 mg, 0.050 mmol, 1.0 equiv) was suspended in 3 mL of dichloromethane. Acetic anhydride (10 μL, 0.006 mmol, 1.2 equiv) and triethylamine (0.020 μL, 0.13 mmol, 2.5 equiv) were added and the reaction was stirred for 48 hours. The solvent was removed in vacuo and the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 367.3 [M+H]⁺.

Example 101 5-[(Methylsulfonyl)amino]-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 100, replacing acetic anhydride with methansulfonic anhydride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 403.2 [M+H]⁺.

Example 102 3-(Morpholin-4-ylsulfonyl)-5-[(trifluoroacetyl)amino]-1H-indole-2-carboxamide

Using the procedure described in Example 101, the title compound was obtained as a side product. Proton NMR for the product was consistent with the titled compound. ESI+MS: 421.2 [M+H]⁺.

Example 103 5-[(2-Aminoethyl)amino]-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 63, replacing 5-formyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide with tert-butyl 2-oxoethylcarbamate and p-methoxyaniline with 5-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, the title compound was obtained as a trifluoroacetate salt, after lyophilization of purified Boc-protected product from preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 367.3 [M+H]⁺.

Example 104 5-(Dimethylamino)-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Example 63, replacing 5-formyl-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide with formaldehyde and p-methoxyaniline with 5-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 353.3 [M+H]⁺.

Example 105 4,5-Dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-amino-4-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

Ethyl 5-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (189 mg, 0.53 mmol, 1.0 equiv) was dissolved in 4 mL of dimethylformamide and cooled to 0° C. N-bromosuccinimide (95 mg, 0.54 mmol, 1.0 equiv) was added and the reaction was stirred for 15 minutes. The reaction mixture was partitioned between dichloromethane and aqueous saturated NaHCO₃, which was extracted three times with dichloromethane. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 50% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 432.1 [M+H]⁺.

Step B: Ethyl 4,5-dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

To a stirring 3 mL acetonitrile solution of ethyl 5-amino-4-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (52 mg, 0.12 mmol, 1.0 equiv), CuBr (35 mg, 0.24 mmol, 2.0 equiv), CuBr₂ (67 mg, 0.30 mmol, 2.5 equiv) and tetrafluoroboric acid (30 mg, 48 weight % solution, 0.18 mmol, 1.5 equiv) was added tert-butyl nitrite (19 μL, 0.16 mmol, 1.3 equiv). The reaction was stirred for 20 minutes at ambient temperature and partitioned between dichloromethane and aqueous saturated NaHCO₃. The aqueous layer was extracted three times with dichloromethane and the combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 100% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 496.9 [M+H]⁺.

Step C: 4,5-Dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 4,5-dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 468.0 [M+H]⁺.

Example 106 5,6-Dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5,6-dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (108 mg, 0.26 mmol, 1.0 equiv) and sodium acetate (64 mg, 0.78 mmol, 3.0 equiv) were dissolved in 2 mL of acetic acid. A 1 mL solution of Br₂ (41 mg, 0.26 mmol, 1.0 equiv) in acetic acid was added dropwise to the mixture and was stirred for 3 hours at ambient temperature, after which the vessel was heated at 50° C. for 18 hours. An additional 1 mL solution of Br₂ (41 mg, 0.26 mmol, 1.0 equiv) in acetic acid was added dropwise to the mixture and stirred at 50° C. for 90 minutes. An additional 1 mL solution of Br₂ (82 mg, 0.52 mmol, 2.0 equiv) was added and the vessel was heated for 30 more minutes. The reaction mixture was partitioned between ethyl acetate and aqueous saturated NaHCO₃, which was extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 496.9 [M+H]⁺.

Step B: 5,6-Dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5,6-dibromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 468.1 [M+H]⁺.

Example 107 5-Bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Step A: Ethyl 5-bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate

Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (56 mg, 0.13 mmol, 1.0 equiv) was dissolved in 3 μL of sulfuric acid and cooled to 0° C. A 1 mL aqueous solution of nitric acid (10 mg, 0.15 mmol, 1.15 equiv) was added dropwise and the reaction was stirred for 10 minutes at 0° C., after which an additional 1 mL aqueous solution of nitric acid (5 mg, 0.06 mmol, 0.5 equiv) was added dropwise. After stirring for 30 minutes, the reaction mixture was partitioned between ethyl acetate and water, which was extracted three times with ethyl acetate. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 15% ethyl acetate/dichloromethane) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 462.0 [M+H]⁺.

Step B: 5-Bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedure described in Step E of Example 1, replacing ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 433.2 [M+H]⁺.

Example 108 5-Bromo-6-nitro-3-(morpholin-4-ylsulfonyl-1H-indole-2-carboxamide

Using the procedures described in Example 107, the title compound was obtained. Ethyl 5-bromo-6-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate was isolated as a minor product from Step A. Proton NMR for the product was consistent with the titled compound. ESI+MS: 433.3 [M+H]⁺.

Example 109 5-Bromo-4-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide

Using the procedures described in Example 47, replacing in Step A ethyl 5-bromo-6-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-4-nitro-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+MS: 403.2 [M+H]⁺.

Example 110 (S)-3-{[2-(Phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide

(S)-5-Bromo-3-{[2-(phenoxymethyl)morpholino-4-yl]sulfonyl}-1H-indole-2-carboxamide (20 mg, 0.040 mmol) was dissolved in 7 mL of EtOH. The vessel was degassed and charged with 10% palladium on carbon (2 mg, 10 weight percent). The vessel was then charged with 1 atm. H₂ and stirred vigorously for 18 hours. The reaction was filtered through a pad of Celite, the pad was washed with EtOH and the filtrate was concentrated in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 416.08 [M+H]⁺.

Example 111 (R,S)-5-Bromo-3-[(2-{[(cyclohexylmethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2-carboxamide

To a 20 mL tube was placed PS-DCC (832 mg, 0.018 mmol, 1.38 mmol/g), HOBt (109 mg, 0.81 mmol), and a 5:1:1 mixture of CHCl₃:CH₃CN:tBuOH. Then, cyclohexylmethyl amine (65 μL, 0.5 mmol) and (R,S)-Boc-2-carboxymorpholine (125 mg, 0.54 mmol) were added, and the vial was placed on a GlasCol orbital rotator for 16 hours. After this time, MP-carbonate (480 mg, 1.62 mmol, 3.38 mmol/g) was added to scavenge the HOBt and excess (R,S)-Boc-2-carboxymorpholine.

Three hours later, the vial's contents were filtered through an Applied Separations filter tube, washed with DCM (3×3 mL) and concentrated in an HTII-12 Genevac unit to afford an yellow oil. This material was then dissolved in DCM (2 mL) and 4 N HCl/dioxane (2 mL) added. After 10 minutes, the solvent was evaporated under a stream of nitrogen gas and purified/free-based by standard SCX SPE.

Concentration provided a colorless oil, N-(cyclohexylmethyl)morpholine-2-carboxamide, 102 mg (90%)—a single peak (214 nm and ELSD) at 2.06 min (CH₃CN/H₂O/1% TFA, 4 min gradient). To an 8 mL vial was placed ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (50 mg, 0.099 mmol), PS-NMM (58 mg, 0.216 mmol, 3.72 mmol/g), PS-DMAP (37 mg, 0.05 mmol, 1.48 mmol/g) and DCM. Then, N-(cyclohexylmethyl)morpholine-2-carboxamide (18 mg, 0.08 mmol) was added, and the vial placed on a GlasCol orbital rotator for 16 hours. After this time, PS-trisamine resin (75 mg, 0.108 mmol, 1.44 mmol/g) was added to the vial to scavenge excess sulfonyl chloride.

Three hours later, the vial's contents were filtered through an Applied Separations filter tube, washed with DCM (3×3 mL) and concentrated in an HTII-12 Genevac unit to afford an yellow solid. This material was then dissolved in 2 M NH₃/EtOH, sealed in a scintillation vial and heated to 90 degrees on a J-KEM heater/shaker block for 3 hours. The vial was then dried in an HTII-12 Genevac unit to afford a brown solid. This material was then purified by Mass Guided HPLC on an Agilent 1100 Purification unit to afford a white crystalline solid.

Analytical LCMS: single peak (214 nm and ELSD) at 3.35 min (CH₃CN/H₂O/1% TFA, 4 min gradient).

¹H NMR (300 MHz, DMSO-d₆): δ 8.2 (s, 2H), 7.99 (s, 1H), 7.39 (m, 2H), 7.48 (m, 2H), 3.95 (t, J=11 Hz, 2H), 3.63 (m, 2H), 3.44 (d, J=11.4 Hz, 1H), 2.48 (m, 2H), 2.3 (t, J=18 Hz, 1H), 1.56 (m, 6H), 1.34 (m, 2H), 1.08 (m, 2H), 0.77 (m, 2H) ppm.

HRMS calc'd for C₂₁H₂₇BrN₄O₅S, 527.0958; found, 527.0940.

The analogs illustrated below were made utilizing the above-described procedure:

Name Structure ESI + MS 5-bromo-3-({2- [(cyclohexylamino) carbonyl]morpholin-4- yl}sulfonyl)-1H-indole-2- carboxamide

514.4 5-bromo-3-({2-[(2,3- dihydro-1H-inden-1- ylamino)carbonyl] morpholin-4-yl}sulfonyl)- 1H-indole-2-carboxamide

548.4 5-bromo-3-[(2-{[(2- phenylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

536.4 5-bromo-3-[(2-{[(3- phenylpropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

550.4 5-bromo-3-[(2-{[3,3- diphenylpropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

626.5 5-bromo-3-{[2-(3,4- dihydroisoquinolin-2(1H)- ylcarbonyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

548.4 5-bromo-3-[(2-{[(2- phenoxyethyl)amino]carbonyl}morpholin-4-yl)sulfonyl]-1H-indole-2- carboxamide

552.4 3-({2-[(3-benzylpyrrolidin- 1-yl)carbonyl]morpholin-4- yl}sulfonyl)-5-bromo-1H- indole-2-carboxamide

576.4 5-bromo-3-[(2-{[(1,2,3,4- tetrahydronaphthalen-2- ylmethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

576.4 3-({2-[(benzylamino) carbonyl]morpholin-4- yl}sulfonyl)-5-bromo-1H- indole-2-carboxamide

522 5-bromo-3-{[2-({[3- (trifluoromethyl)benzyl] amino}carbonyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

590 5-bromo-3-[(2-{[(2,2- diphenylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

612.5 5-bromo-3-({2-[(2,3- dihydro-1H-inden-2- ylamino)carbonyl] morpholin-4-yl}sulfonyl)- 1H-indole-2-carboxamide

548.4 3-[(7-benzyl-2,7- diazaspiro[4.4]non-2- yl)sulfonyl]-5-bromo-1H- indole-2-carboxamide

632.4 5-bromo-3-{[2-({[(5- methylpyrazin-2- yl)methyl]amino} carbonyl)morpolin-4- yl]sulfonyl}-1H-indole-2- carboxamide

538.4 5-bromo-3-[(2-{[(pyridin-3- ylmethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

637.4 5-bromo-3-[(2-{[(1- phenylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

536.4 5-bromo-3-{[2-({[3-(1H- imidazol-1-yl)propyl] amino}carbonyl) morpholin-4-yl]sulfonyl}-1H- indole-2-carboxamide

654.4 5-bromo-3-{[2-({[(1R)-1- phenylethyl]amino} carbonyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

536.4 5-bromo-3-[(2-{[(2- phenylpropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

550.4 3-[(2- {[benzyl(methyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-5-bromo-1H- indole-2-carboxamide

536.4 3-({2-[(4-benzylpiperazin-1- yl)carbonyl]morpholin-4- yl}sulfonyl)-5-bromo-1H- indole-2-carboxamide

705.5 5-bromo-3-[(2-{[(pyridin- 2-ylmethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

637.4 5-bromo-3-{[2-({[2-(tert- butylthio)ethyl]amino} carbonyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

548.4 3-({2-[(benzhydrylamino) carbonyl]morpholin-4- yl}sulfonyl)-5-bromo-1H- indole-2-carboxamide

598.4 5-bromo-3-{[2-({[(2S)-2- phenylcyclopropyl]amino} carbonyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

548.4 5-bromo-3-({2-[(3- phenylpyrrolidin-1- yl)carbonyl]morpholin-4- yl}sulfonyl)-1H-indole-2- carboxamide

562.4 5-bromo-3-({2-[(4,4- diphenylpiperidin-1- yl)carbonyl]morpholin-4- yl}sulfonyl)-1H-indole-2- carboxamide

652.5 5-bromo-3-[(2-{[(2,3- dihydro-1H-inden-2- ylmethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

562.4 5-bromo-3-({2-[(2,3- dihydro-1H-inden-1- ylamino)carbonyl] morpholin-4-yl}sulfonyl)- 1H-indole-2-carboxamide

548.4 5-bromo-3-({2-[(2,3- dihydro-1H-inden-1- ylamino)carbonyl] morpholin-4-yl}sulfonyl)- 1H-indole-2-carboxamide

548.4 5-bromo-3-({2-[(3-pyridin- 4-ylpyrrolidin-1- yl)carbonyl]morpholin-4- yl}sulfonyl)-1H-indole-2- carboxamide

563.4 5-bromo-3-[(2-{[(2- hydroxy-2,3-dihydro-1H- inden-1- yl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

564.4 5-bromo-3-({2-[(4- hydroxy-4-phenylpiperidin- 1-yl)carbonyl]morpholin-4- yl}sulfonyl)-1H-indole-2- carboxamide

592.4 3-{[2- (anilinocarbonyl)morpholin- 4-yl]sulfonyl}-5-bromo- 1H-indole-2-carboxamide

508 5-bromo-3-[(2-{[(2-oxo-2- phenylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

550.4 5-bromo-3-({2- [(neopentylamino)carbonyl] morpholin-4-yl}sulfonyl)- 1H-indole-2-carboxamide

502.4 5-bromo-3-[(2-{[(1,2- diphenylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

612.5 5-bromo-3-[(2-{[(4- chlorophenyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

542.8 5-bromo-3-[(2-{[(4- phenoxyphenyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

600.4 5-bromo-3-[(2-{[(4-tert- butylphenyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

564.4 5-bromo-3-{[2-({[3-(2- oxopyrrolidin-1- yl)propyl]amino}carbonyl) morpholin-4-yl]sulfonyl}- 1H-indole-2-carboxamide

557.4 5-bromo-3-[(2-{[(3- isopropoxypropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

532.4 5-bromo-3-[(2-{[(3- ethoxypropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

518.4 5-bromo-3-[(2-{[(2- cyclohex-1-en-1- ylethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

540.4 5-bromo-3-[(2- {[(2,2,3,3,4,4,4- heptafluorobutyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

614.3 5-bromo-3-[(2-{[(3- isobutoxypropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

546.4 5-bromo-3-[(2-{[(3- butoxypropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

546.4 5-bromo-3-[(2-{[(2-thien- 2-ylethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

542.4 3-[(2-{[(1H-benzimidazol- 2-ylmethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-5-bromo-1H- indole-2-carboxamide

676.4 3-{[2-(azepan-1- ylcarbonyl)morpholin-4- yl]sulfonyl}-5-bromo-1H- indole-2-carboxamide

514.4 5-bromo-3-({2-[({2-[(2,6- dichlorobenzyl)thio]ethyl} amino)carbonyl]morpholin- 4-yl}sulfonyl)-1H-indole-2- carboxamide

651.4 3-{[2-({[4- (aminosulfonyl)benzyl] amino}carbonyl)morpholin- 4-yl]sulfonyl}-5-bromo- 1H-indole-2-carboxamide

601.4 5-bromo-3-{[2- (thiomorpholin-4- ylcarbonyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

518.4 5-bromo-3-[(2-{[(2- methoxyethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

490 5-bromo-3-[(2-{[(2- methoxy-1- methylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

504 5-bromo-3-[(2-{[(1- ethylpropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

502.4 5-bromo-3-{[2-({[6- (dimethylamino)hexyl] amino}carbonyl)morpholin- 4-yl]sulfonyl}-1H-indole- 2-carboxamide

559.5 5-bromo-3-[(2- {[(tetrahydrofuran-2- ylmethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

516 5-bromo-3-[(2-{[(1- phenylcyclopropyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

548.4 5-bromo-3-{[2- ({[phenyl(pyridin-4- yl)methyl]amino}carbonyl) morpholin-4-yl]sulfonyl}- 1H-indole-2-carboxamide

599.4 5-bromo-3-[(2- {[(dicyclopropylmethyl) amino]carbonyl}morpholin- 4-yl)sulfonyl]-1H-indole- 2-carboxamide

526.4 5-bromo-3-[(2-{[(1,4- dioxan-2- ylmethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

532 5-bromo-3-{[2-({methyl [2-(4-methylphenoxy)ethyl] amino}carbonyl)morpholin- 4-yl]sulfonyl}-1H-indole- 2-carboxamide

580.4 5-bromo-3-{[2-({[(1,1- dioxidotetrahydrothien-3- yl)methyl]amino}carbonyl) morpholin-4-yl]sulfonyl}- 1H-indole-2-carboxamide

563.4 5-bromo-3-[(2-{[2-(2- phenylethyl)pyrrolidin-1- yl]carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

590.5 5-bromo-3-[(2-{[(2- cyclohexylethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

542.4 5-bromo-3-{[2-({[(1- methyl-1H-imidazol-4- yl)methyl]amino}carbonyl) morpholin-4-yl]sulfonyl}- 1H-indole-2-carboxamide

640.4 5-bromo-3-[(2-{[(1,1- dioxidotetrahydrothien-3- yl)amino]carbonyl} morpholin-4-yl)sulfonyl]-1H- indole-2-carboxamide

550.4 5-bromo-3-[(2-{[(1- naphthylmethyl)amino] carbonyl}morpholin-4- yl)sulfonyl]-1H-indole-2- carboxamide

572.4 5-bromo-3-[(2- {[(imidazo[2,1- b][1,3]thiazol-6- ylmethyl)amino]carbonyl} morpholin-4-yl)sulfonyl]- 1H-indole-2-carboxamide

568.4 3-[(2-{[2-(1,3-benzothiazol-2- yl)pyrrolidin-1- yl]carbonyl}morpholin-4- yl)sulfonyl]-5-bromo-1H- indole-2-carboxamide

619.5 5-bromo-3-({2- [(cyclopropylamino) carbonyl]morpholin-4- yl}sulfonyl)-1H-indole-2- carboxamide

472

Example 112 5-Bromo-3-{[4-(3-phenylpropyl)piperidin-1-yl]sulfonyl}-1H-indole carboxamide

To an 8 mL vial was placed ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate (50 mg, 0.099 mmol), PS-NMM (58 mg, 0.216 mmol, 3.72 mmol/g), PS-DMAP (37 mg, 0.05 mmol, 1.48 mmol/g) and DCM. Then, 4-(3-phenylpropyl)piperidine (26 mg, 0.08 mmol) was added, and the vial placed on a GlasCol orbital rotator for 16 hours. After this time, PS-trisamine resin (75 mg, 0.108 mmol, 1.44 mmol/g) was added to the vial to scavenge excess sulfonyl chloride.

Three hours later, the vial's contents were filtered through an Applied Separations filter tube, washed with DCM (3×3 mL) and concentrated in an HTII-12 Genevac unit to afford an yellow solid. This material was then dissolved in 2 M NH₃/EtOH, sealed in a scintillation vial and heated to 90 degrees on a J-KEM heater/shaker block for 3 hours. The vial was then dried in an HTII-12 Genevac unit to afford a brown solid. This material was then purified by Mass Guided HPLC on an Agilent 1100 Purification unit to afford a white crystalline solid.

Analytical LCMS: single peak (214 nm and ELSD) at 3.94 min (CH₃CN/H₂O/1% TFA, 4 min gradient).

¹H NMR (300 MHz, DMSO-d₆): δ 8.26 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.69 (m, 1H), 7.63 (m, 1H), 7.47 (m, 1H), 7.2 (m, 2H), 7.13 (m, 3H), 3.59 (m, 2H), 3.2 (m, 2H), 2.18 (m, 3H), 1.66 (d, J=11.7 Hz, 2H), 1.46 (m, 2H), 1.13 (m, 2H) ppm.

HRMS calc'd for C₂₃H₂₆BrN₃O₃S, 504.0951; found, 504.0944.

The analogs illustrated in the table below were prepared utilizing the procedures described above.

ESI + Name Structure MS 5-chloro-3-({2-[(2- ethoxyphenoxy)methyl] morpholin-4-yl}sulfonyl)-1H- indole-2-carboxamide

495 5-chloro-3-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]hept-5- ylsulfonyl]-1H-indole-2- carboxamide

357 3-[(7-benzyl-9-thia-3,7- diazabicyclo[3.3.1]non-3- yl)sulfonyl]-5-chloro-1H-indole-2- carboxamide

606 5-chloro-3-{[2-(1H-indol-4- yl)morpholin-4-yl]sulfonyl}-1H- indole-2-carboxamide

460 5-chloro-3-(2,3-dihydro-1,4- benzoxazepin-4(5H)-ylsulfonyl)- 1H-idole-2-carboxamide

407 3-[(benzofuran-yl-1-oxa-8- azaspiro[4.5]dec-8-yl)sulfonyl]-5- chloro-1H-indole-2-carboxamide

447 5-chloro-3-{[4-fluoro-4-(3- phenylpropyl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

479 3-[(3-benzyl-1-oxa-8- azaspiro[4.5]dec-8-yl)sulfonyl]-5- chloro-1H-indole-2-carboxamide

489 3-({4-[(benzyloxy)methyl]-4- phenylpiperidin-1-yl}sulfonyl)-5- chloro-1H-indole-2-carboxamide

539 5-chloro-3-{[4-hydroxy-4-(3- phenylpropyl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

477 5-chloro-3-{[7-(4-chlorophenyl)- 2,7-diazaspiro[4.4]non-2- yl]sulfonyl}-1H-indole-2- carboxamide

608.4 5-chloro-3-{[3-(4-methyl-4H- 1,2,4-triazol-3-yl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

538 5-chloro-3-{[3-(2- phenylethyl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

447 5-chloro-3-{[3-(2- phenylethyl)pyrrolidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

433 5-chloro-3-{[4-(cyclopropyl{[3- (trifluoromethyl)phenyl]sulfonyl} amino)piperidin-1-yl]sulfonyl}-1H- indole-2-carboxamide

606 5-chloro-3-({2-[(4- chlorophenoxy)methyl]morpholin- 4-yl}sulfonyl)-1H-indole-2- carboxamide

485.4 tert-butyl (1-{[2-(aminocarbonyl)- 5-chloro-1H-indol-3- yl]sulfonyl}piperidin-3-yl)acetate

457 3-[(3-benzylpiperidin-1- yl)sulfonyl]-5-chloro-1H-indole-2- carboxamide

433 5-chloro-3-{[3-(2- methylphenyl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

433 5-chloro-3-({4-[2- (dimethylamino)ethyl]piperidin-1- yl}sulfonyl)-1H-indole-2- carboxamide

528 ethyl 1′-{[2-(aminocarbonyl)-5- chloro-1H-indol-3-yl]sulfonyl}- 1,4′-bipiperidine-3-carboxylate

612 5-bromo-3-{[3-(4-tert- butoxybenzyl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

549.5 5-bromo-3-{[4-(3- phenylpropyl)piperidin-1- yl]sulfonyl}-1H-indole-2- carboxamide

505.4 5-bromo-N-methoxy-N-methyl-3- {[2-(phenoxymethyl)morpholin-4- yl]sulfonyl}-1H-indole-2- carboxamide

539.4

Assays

The compounds of the instant invention described in the Examples above were tested by the assays described below and were found to have kinase inhibitory activity. In particular, the compounds of the instant invention inhibited IGF-1R or insulin receptor kinase activity with an IC₅₀ of less than or equal to about 100 μM. Other assays are known in the literature and could be readily performed by those with skill in the art (see for example, Dhanabal et al., Cancer Res. 59:189-197; Xin et al., J. Biol. Chem. 274:9116-9121; Sheu et al., Anticancer Res. 18:4435-4441; Ausprunk et al., Dev. Biol. 38:237-248; Gimbrone et al., J. Natl. Cancer Inst. 52:413-427; Nicosia et al., In Vitro 18:538-549).

IGF-1R Kinase Assay

IGF-1R receptor kinase activity is measured by incorporation of phosphate into a peptide substrate containing a tyrosine residue. Phosphorylation of the peptide substrate is quantitated using anti-IGF-1R and anti-phosphotyrosine antibodies in an HTRF (Homogeneous Time Resolved Fluorescence) detection system. (Park, Y-W., et al. Anal. Biochem., (1999) 269, 94-104)

Materials IGF-1R Receptor Kinase Domain

The intracellular kinase domain of human IGF-1R was cloned as a glutathione S-transferase fusion protein. IGF-1R β-subunit amino acid residues 930 to 1337 (numbering system as per Ullrich et al., EMBO J. (1986) 5, 2503-2512) were cloned into the baculovirus transfer vector pAcGHLT-A (BD-Pharmingen) such that the N-terminus of the IGF-1R residues are fused to the C-terminus of the GST domain encoded in the transfer vector pAcGHLT-A. Recombinant virus was generated and the fusion protein expressed in SF-9 insect cells (BD-Pharmingen). Enzyme was purified by means of a glutathione sepharose column.

Insulin Receptor Kinase Domain

The intracellular kinase domain of human insulin receptor was cloned as a glutathione S-transferase fusion protein. Insulin receptor β-subunit amino acid residues 941 to 1343 (numbering system as per Ullrich et al., Nature, (1985) 313, 756-761) were cloned into the baculovirus transfer vector pAcGHLT-A (BD-Pharmingen) such that the N-terminus of the IGF-1R residues are fused to the C-terminus of the GST domain encoded in the transfer vector pAcGHLT-A. Recombinant virus was generated and the fusion protein expressed in SF-9 insect cells (BD-Pharmingen) Enzyme was purified by means of a glutathione sepharose column.

Insect Cell Lysis Buffer

10 mM Tris pH 7.5; 130 mM NaCl; 2 mM DTT; 1% Triton X-100; 10 mM NaF; 10 mM NaPi; 10 mM NaPPi; 1× protease inhibitor cocktail (Pharmingen).

Wash Buffer

Phosphate Buffered Saline (PBS): 137 Mm NaCl, 2.6 mM KCl, 10 mM Na₂HPO₄, 1.8 mM KH₂PO₄, pH 7.4; 1 mM DTT; 1× protease inhibitor cocktail

Dialysis Buffer

20 mM Tris pH 7.5; 1 mM DTT; 200 mM NaCl; 0.05% Triton X-100 and 50% glycerol

Enzyme Dilution Buffer

50 mM Tris pH 7.5; 1 mM DTT; 100 mM NaCl; 10% glycerol; 1 mg/ml BSA

Enzyme Reaction Buffer

20 mM Tris pH 7.4; 100 mM NaCl; 1 mg/ml BSA; 5 mM MgCl₂; 2 mM DTT

Quench Buffer

125 mM Tris pH 7.8; 75 mM EDTA; 500 mM KF; 0.125% Triton X-100; 1.25% BSA; 60 nM SA-XL665 (Packard); 300 pM europium cryptate labeled anti-phosphotyrosine antibody (Eu-PY20)

Peptide Substrate

Sequence LCB-EQEDEPEGDYFEWLE-NH₂; stock solution is 1 mM dissolved in DMSO; diluted to 1 uM in 1× enzyme reaction buffer for 10× working stock. (LCB=aminohexanoylbiotin)

ATP

Stock solution is 0.5 M ATP (Boehringer) pH 7.4; stock solution is diluted to 40 mM ATP in enzyme reaction buffer to give 20× working stock solution

HEK-21 Cell Line

Human embryonic kidney cells (HEK-293) (ATCC) were transfected with an expression plasmid containing the entire IGF-1R coding sequence. After antibiotic selection, colonies were screened for IGF-1R overexpression by western blot analysis. One clone, designated HEK-21 was selected for cell based IGF-1R autophosphoryl-ation assays.

HEK Cell Growth Media

Dulbecco's Modified Eagle's Media (DMEM), 10% Fetal Calf Serum, 1× Penn/Strep, 1× Glutamine, 1× Non-essential amino acids (all from Life Technologies)

Cell Lysis Buffer

50 mM Tris-HCl pH 7.4; 150 mM NaCl; 1% Triton X-100 (Sigma); 1× Mammalian protease inhibitors (Sigma); 10 mM NaF; 1 mM NaVanadate

Western Blocking Buffer 20 mM Tris-HCl pH 8.0; 150 mM NaCl; 5% BSA (Sigma); 0.1% Tween 20 (Biorad) Methods A. Protein Purifications

Spodoptera frugiperda SF9 cells were transfected with recombinant virus encoding either the GST-IGF-1R β-subunit or GST-InsR fusion protein at an MOI of 4 virus particles/cell. Cells are grown for 48 hours at 27° C., harvested by centrifugation and washed once with PBS. The cell pellet is frozen at −70° C. after the final centrifugation. All subsequent purification steps are performed at 4° C. 10 grams of frozen cell paste is thawed in a 90 ml volume of insect cell lysis buffer (BD-Pharmingen) and held on ice with occasional agitation for 20 minutes. The lysate is centrifuged at 12000 g to remove cellular debris. Lysis supernatant was mixed with 45 ml of glutathione agarose beads (BD-Pharmingen) and agitated slowly at 4° C. for one hour after which the beads were centrifuged and washed 3× with wash buffer. The beads are resuspended in 45 ml of wash buffer and poured as a slurry into a chromatography column. The column is washed with 5 volumes of wash buffer and the GST-IGF-1R is eluted from the column with 5 mM Glutathione in wash buffer. Pooled fractions are dialyzed vs. dialysis buffer and stored at −20° C. IGF-1R KINASE ASSAY

The IGF-1R enzyme reaction is run in a 96 well plate format. The enzyme reaction consists of enzyme reaction buffer plus 0.1 nM GST-IGF-1R, 100 nM peptide substrate and 2 mM ATP in a final volume of 60 microliters. Inhibitor, in DMSO, is added in a volume 1 microliter and preincubated for 10 minutes at 22° C. Final inhibitor concentration can range from 100 uM to 1 nM. The kinase reaction is initiated with 3 microliters of 40 mM ATP. After 20 minutes at 22° C., the reaction is stopped with 40 microliters of quench buffer and allowed to equilibrate for 2 hours at 22° C. Relative fluorescent units are read on a Discovery plate reader (Packard). IC50s for compounds are determined by 4 point sigmoidal curve fit.

B. Insulin Receptor Kinase Assay

The kinase reaction for insulin receptor is identical to that used to assay IGF-1R (above), except that GST-InsR is substituted at a final concentration of 0.1 nM.

C. Cell Based IGF-1R Autophosphorylation Assay

IGF-1R inhibitor compounds are tested for their ability to block IGF-I induced IGF-1R autophosphorylation in a IGF-1R transfected human embryonic kidney cell line (HEK-21). HEK-21 cells over-expressing the human IGF-1R receptor are cultured in 6-well plates (37° C. in a 5% CO₂ atmosphere) in HEK cell growth media to 80% of confluence. Cells are serum starved for four hours in HEK growth media with 0.5% fetal calf serum. A 10× concentration of inhibitor in growth media is added to the cells in one-tenth the final media volume and allowed to preincubate for one hour at 37° C. Inhibitor concentration can range from 10 nM to 100 uM. IGF-I (Sigma) is added to the serum starved cells to a final concentration of 30 ng/ml. After a 10 minute incubation in the presence of IGF-I at 37° C., the media is removed, the cells washed once with PBS and 0.5 mls of cold cell lysis buffer added. After 5 minutes incubation on ice, cells are scraped from the wells and lysis buffer plus cells are transferred to a 1.5 ml microfuge tube. The total lysate is held at 4° C. for twenty minutes and then centrifuged at top speed in a microfuge. The supernatant is removed and saved for analysis. Phosphorylation status of the receptor is assessed by Western blot. Lysates are electrophoresed on 8% denaturing Tris-Glycine polyacrylamide gels and the proteins transferred to nitrocellulose filters by electro-blotting. The blots are blocked with blocking reagent for 10 minutes after which anti-phosphotyrosine antibody (4G10, Upstate Biotechnology) is added to a final dilution of 1:1500. Blots and primary antibody are incubated at 4° C. overnight. After washing with PBS plus 0.2% Tween 20 (Biorad), an HRP conjugated anti-mouse secondary antibody (Jackson Labs) is added at a dilution of 1:15000 and incubated at 4° C. for 2 hours. Blots are then washed with PBS-Tween and developed using ECL (Amersham) luminescent reagent. Phosphorylated IGF-1R on the blots is visualized by autoradiography or imaging using a Kodak Image Station 440. IC50s are determined through densitometric scanning or quantitation using the Kodak Digital Science software. 

1. A compound of Formula I:

wherein: Y is selected from:

R^(a) is independently selected from: 1) H, 2) C₁-C₆ alkyl, 3) Halogen, 4) Aryl, 5) Heterocycle, 6) C₃-C₁₀ cycloalkyl, and 7) OR⁴; said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent selected from R⁷; R¹ is independently selected from: 1) H, 2) (CR^(a) ₂)_(n)R⁶, 3) (CR^(a) ₂)_(n)C(O)R⁴, 4) C(O)N(R⁴)₂, 5) (CR^(a) ₂)_(n)OR⁴, 6) (CR^(a) ₂)_(n)N(R⁴)₂, 7) S(O)_(m)R⁶, 8) S(O)_(m)R⁶OR⁴, 9) C(O)N(R⁴)(CR^(a) ₂)_(n)R⁶, 10) C(O)N(R⁴)(CR^(a) ₂)_(n)OR⁴, 11) C(O)R⁶(CR^(a) ₂)_(n)R⁶, 12) C(O)N(R⁴)(CR^(a) ₂)_(n)S(O)_(m)(CR^(a) ₂)_(n)R⁶, 13) C(O)N(R⁴)(CR^(a) ₂)_(n)C(O)R⁶, 14) C(O)N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂, 15) Halogen, 16) N(R⁴)S(O)_(m)R⁶, and (CR^(a) ₂)_(n)C(O)OR⁴; R² is: 1) H, 2) unsubstituted or substituted C₁-C₁₀ alkyl, 3) N(R⁴)₂, 4) OR⁴, 5) unsubstituted or substituted aryl, and 6) unsubstituted or substituted C₃-C₁₀ cycloalkyl; R⁴ is independently selected from: 1) H, 2) C₁-C₆ alkyl, 3) C₃-C₁₀ cycloalkyl, 4) Aryl, 5) Heterocycle, 6) CF₃, 7) C₂-C₆ alkenyl, and 8) C₂-C₆ alkynyl; said alkyl, cycloalkyl, aryl, heterocycle, alkenyl and alkynyl is optionally substituted with at least one substituent selected from R⁷; R⁵ is independently selected from: 1) H, 2) Halogen, 3) NO₂, 4) CN, 5) CR⁴═C(R⁴)₂, 6) C≡CR⁴ 7) (CR^(a) ₂)_(n)OR⁴, 8) (CR^(a) ₂)_(n)N(R⁴)₂, 9) C(O)R⁴, 10) C(O)OR⁴, 11) (CR^(a) ₂)_(n)R⁴, 12) S(O)_(m)R⁶, 13) S(O)_(m)N(R⁴)₂, 14) OS(O)_(m)R⁶, 15) N(R⁴)C(O)R⁴, 16) N(R⁴)S(O)_(m)R⁶, 17) (CR^(a) ₂)_(n)N(R⁴)R⁶, 18) (CR^(a) ₂)_(n)N(R⁴)R⁶OR⁴, 19) (CR^(a) ₂)_(n)N(R⁴)(CR^(a) ₂)_(n)C(O)N(R⁴)₂, 20) N(R⁴)(CR^(a) ₂)_(n)R⁶, 21) N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂, 22) (CR^(a) ₂)_(n)C(O)N(R⁴)₂, 23) O(CR^(a) ₂)_(n)C(O)OR⁴, and 24) O(CR^(a) ₂)_(n)C(O)N(R⁴)₂; R⁶ is independently selected from: 1) C₁-C₆ alkyl, 2) Aryl, 3) Heterocycle, and 4) C₃-C₁₀ cycloalkyl; said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent of R⁷; R⁷ is independently selected from: 1) Unsubstituted or substituted C₁-C₆ alkyl, 2) Halogen, 3) OR⁴, 4) CF₃, 5) Unsubstituted or substituted aryl, 6) Unsubstituted or substituted C₃-C₁₀ cycloalkyl, 7) Unsubstituted or substituted heterocycle, 8) S(O)_(m)N(R⁴)₂, 9) C(O)OR⁴, 10) C(O)R⁴, 11) CN, 12) C(O)N(R⁴)₂, 13) N(R⁴)C(O)R⁴, 14) NO₂; and 15) S(O)_(m)R⁶; m is independently 0, 1 or 2; n is independently 0, 1, 2, 3, 4, 5 or 6; s is 0 to 6; t is 0, 1, or 2; v is 0, 1 or 2; w is 0, 1, 2, 3, or 4; z is 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof.
 2. The compound according to claim 1, wherein: R^(a) is independently selected from: 1) H, 2) C₁-C₆ alkyl, 3) Halogen, 4) Aryl, 5) Heterocycle, 6) C₃-C₁₀ cycloalkyl, and 7) OR⁴; said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent selected from R⁷; R¹ is independently selected from: 1) H, 2) (CR^(a) ₂)_(n)R⁶, 3) (CR^(a) ₂)_(n)C(O)R⁴, 4) C(O)N(R⁴)₂, 5) (CR^(a) ₂)_(n)OR⁴, 6) (CR^(a) ₂)_(n)N(R⁴)₂, 7) S(O)_(m)R⁶, 8) S(O)_(m)R⁶OR⁴, 9) C(O)N(R⁴)(CR^(a) ₂)_(n)R⁶, 10) C(O)N(R⁴)(CR^(a) ₂)_(n)OR⁴ 11) C(O)R⁶(CR^(a) ₂)_(n)R⁶, 12) C(O)N(R⁴)(CR^(a) ₂)_(n)S(O)_(m)(CR^(a) ₂)_(n)R⁶ 13) C(O)N(R⁴)(CR^(a) ₂)_(n)C(O)R⁶, 14) C(O)N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂, 15) Halogen, 16) N(R⁴)S(O)_(m)R⁶, and 17) (CR^(a) ₂)_(n)C(O)OR⁴; R² is: 1) H, 2) Unsubstituted or substituted C₁-C₁₀ alkyl, 3) N(R⁴)₂, or 4) OR⁴; R⁴ is independently selected from: 1) H, 2) C₁-C₆ alkyl, 3) C₃-C₁₀ cycloalkyl, 4) Aryl, 5) Heterocycle, 6)CF₃, 7) C₂-C₆ alkenyl, and 8) C₂-C₆ alkynyl; said alkyl, cycloalkyl, aryl, heterocycle, alkenyl and alkynyl is optionally substituted with at least one substituent selected from R⁷; R⁵ is independently selected from: 1) H, 2) Halogen, 3) NO₂, 4) CN, 5) CR⁴═C(R⁴)₂, 6) C≡CR⁴ 7) (CR^(a) ₂)_(n)OR⁴, 8) (CR^(a) ₂)_(n)N(R⁴)₂, 9) C(O)R⁴, 10) C(O)OR⁴, 11) (CR^(a) ₂)_(n)R⁴, 12) S(O)_(m)R⁶, 13) S(O)_(m)N(R⁴)₂, 14) OS(O)_(m)R⁶, 15) N(R⁴)C(O)R⁴, 16) N(R⁴)S(O)_(m)R⁶, 17) (CR^(a) ₂)_(n)N(R⁴)R⁶, 18) (CR^(a) ₂)_(n)N(R⁴)R⁶OR⁴, 19) (CR^(a) ₂)_(n)N(R⁴)(CR^(a) ₂)_(n)C(O)N(R⁴)₂, 20) N(R⁴)(CR^(a) ₂)_(n)R⁶, 21) N(R⁴)(CR^(a) ₂)_(n)N(R⁴)₂, and 22) (CR^(a) ₂)_(n)C(O)N(R⁴)₂; R⁶ is independently selected from: 1) C₁-C₆ alkyl, 2) Aryl, 3) Heterocycle, and 4) C₃-C₁₀ cycloalkyl; said alkyl, aryl, heterocycle and cycloalkyl is optionally substituted with at least one substituent of R⁷; R⁷ is independently selected from: 1) Unsubstituted or substituted C₁-C₆ alkyl, 2) Halogen, 3) OR⁴, 4) CF₃, 5) Unsubstituted or substituted aryl, 6) Unsubstituted or substituted C₃-C₁₀ cycloalkyl, 7) Unsubstituted or substituted heterocycle, 8) S(O)_(m)N(R⁴)₂, 9) C(O)OR⁴, 10) C(O)R⁴, 11) CN, 12) C(O)N(R⁴)₂, 13) N(R⁴)C(O)R⁴, 14) S(O)_(m)R⁶, and 15) NO₂; m is independently 0, 1 or 2; n is independently 0, 1, 2, 3, 4, 5 or 6; s is 0 to 6; w is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or stereoisomer thereof.
 3. The compound according to claim 2 wherein: R^(a) is independently selected from: 1) H, 2) C₁-C₆ alkyl, 3) Aryl, and 4) C₃-C₁₀ cycloalkyl; said alkyl, aryl, and cycloalkyl is optionally substituted with at least one substituent selected from R⁷; R¹ is independently selected from: 1) H, 2) (CR^(a) ₂)_(n)R⁶, 3) (CR^(a) ₂)_(n)C(O)R⁴, 4) C(O)N(R⁴)₂, 5) (CR^(a) ₂)_(n)OR⁴, 6) (CR^(a) ₂)_(n)N(R⁴)₂, 7) S(O)_(m)R⁶, 8) S(O)_(m)R⁶OR⁴, 9) C(O)N(R⁴)(CR^(a) ₂)_(n)R⁶, 10) C(O)N(R⁴)(CR^(a) ₂)_(n)OR⁴, 11) N(R⁴)S(O)_(m)R⁶, and 12) (CR^(a) ₂)_(n)C(O)OR⁴, R² is: 1) N(R⁴)₂, or 2) OR⁴; s is 0 to 3; or a pharmaceutically acceptable salt or stereoisomer thereof.
 4. The compound according to claim 3 wherein: R¹ is independently selected from: 1) H, 2) (CR^(a) ₂)_(n)R⁶, 3) (CR^(a) ₂)_(n)C(O)R⁴, 4) C(O)N(R⁴)₂, 5) (CR^(a) ₂)_(n)OR⁴, 6) (CR^(a) ₂)_(n)N(R⁴)₂, 7) S(O)_(m)R⁶, and 8) S(O)_(m)R⁶OR⁴; or a pharmaceutically acceptable salt or stereoisomer thereof.
 5. (canceled)
 6. (canceled)
 7. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.
 8. (canceled)
 9. (canceled)
 10. (canceled)
 11. (canceled)
 12. (canceled)
 13. A method of treating cancer in a mammal in need of such treatment comprising administering to said mammal a therapeutically effective amount of a compound of claim
 1. 14. (canceled)
 15. A method of treating cancer which comprises administering a therapeutically effective amount of a compound of claim 1 in combination with a second compound selected from: 1) an estrogen receptor modulator, 2) an androgen receptor modulator, 3) retinoid receptor modulator, 4) a cytotoxic agent, 5) an antiproliferative agent, 6) a prenyl-protein transferase inhibitor, 7) an HMG-CoA reductase inhibitor, 8) an HIV protease inhibitor, 9) a reverse transcriptase inhibitor, and 10) an angiogenesis inhibitor.
 16. The method of claim 15, wherein the second compound is an estrogen receptor modulator selected from tamoxifen and raloxifene.
 17. (canceled)
 18. The method of claim 15 wherein radiation therapy is also administered.
 19. (canceled)
 20. (canceled)
 21. (canceled)
 22. (canceled) 